CA2122992A1

CA2122992A1 - Leukotriene-b derivatives, process for preparing the same and medicaments

Info

Publication number: CA2122992A1
Application number: CA002122992A
Authority: CA
Inventors: Werner Skuballa; Bernd Buchmann; Josef Heindl; Wolfgang Frohlich; Roland Ekerdt; Claudia Giesen
Original assignee: Individual
Current assignee: Bayer Pharma AG
Priority date: 1991-11-29
Filing date: 1992-11-19
Publication date: 1993-06-10
Also published as: PT101093A; DK0614457T3; HUT70477A; US5502075A; NO941978D0; ATE141593T1; NO941978L; WO1993011105A1; AU676670B2; ES2093280T3; HU9401458D0; DE59206968D1; AU2943592A; EP0614457B1; GR3021761T3; EP0614457A1; JPH07505129A

Abstract

ABSTRACT OF THE DISCLOSURE

Leukotriene-B4 derivatives have the formula (1), in which R1 stands for CH2OH, CH3, CF3, COOR5, CONR6R7, or R1 represents together with R2 a carbonyl group; R2 and R3 are different or the same and stand for H or an organic acid residue with 1-15 C atoms; R4 stands for H, C1-C10-alkyl, possibly substituted one or several times by chlorine or bromine, C3-C10-cycloalkyl, a C6-C10-aryl residue possible independently substituted one or several times by chlorine, bromine, phenyl, C1-C4-alkyl, C1-C4-alkoxy, fluoromethyl, chloromethyl, trifluoromethyl, carboxy or hydroxy or a 5-6 membered aromatic heterocyclic ring with at least 1 heteroatom; R5 stands for hydrogen, C1-C10-alkyl, C3-C10-cycloalkyl, an aryl residue possibly substituted by 1-3 chlorine, bromine, phenyl, C1-C4-alkyl, C1-C4-alkoxy, fluoromethyl, chloromethyl, trifluoromethyl, carboxy or hydroxy, CH2-CO-(C6-C10)aryl or a 5-6 membered ring with at least 1 heteroatom; A stands for a trans, trans-CH=CH-CH=CH, -CH2CH2-CH=CH- or a tetramethylene group; B stands for a straight or branched chain C1-C10alkylene group, possibly substituted with fluorine or the group (a); D is a direct bond, oxygen, sulphur, -C?C-, -CH = CR8 or it may represent together with B a direct bond: R6 and R7 are different or the same and stand for H or C1-C4-alkyl or R7 stands for H and R6 stands for C1-C10-alkanoyl or C1-C10-alkansulphonyl; R8 stands for H, C1-C5-alkyl, chlorine, bromine; m stands for the digits 1 or 4 and n equals 3-5. Also disclosed are the salts of these derivatives with physiologically tolerable bases, when R5 stands for hydrogen, and their cyclodextrine clathrates.

Description

2 ~ 9 ~

ew Leukotrie~e-B4 Derivati~e~, Pro~s for their ~roductio~
a~d their ~se a~ Pharmaceutical ~ge~t~

The invention relates to new leukotriene-B4 derivatives, process for their production as well as their use as pharmaceutical agents. The new compounds are structural analogs of preYiously known leukotriene-B4 antagonists, that contain a six-membered ring as a basic structural element (DE-A 39 17 597).
Leukotriene B4 (LTB4) was discovered by B. Samuelsson et al. as a metabolite of arachidonic acid. In the biosynthesis, leukotriene A4 is formed by the enzyme 5-lipoxygenase first as a central intermediate product, which then is converted by a speci~ic hydrolase to the ~TB4.

2:~22~92 OOH
COOE ~C~ COO~
< L~poxygenase <

il Ara~idor~ic Acld ~ 5 Debyd~ase ~COOH

Leukotriene A4 (LrA4) \Hydrolase Gluta~ione ¦ \~ H O~ ~ L

S-transferase 1 Cs~

HO H I,eukotriene R4 ~L1134) COOH

Cys - Gly ~ - Gh Leukotriene C4 ~LI~,~) ..
~ ' r ~ 3 ~ 2122~2 The nomenclature of the leukotriPnes can be gathered from the following works:
a) B. Samuelsson et al~, Prostaglandins 19, 645 (1980~, 17, 785 (1979).
b) C. N. Serhan et al., Prost;aglandins 34, 201 (1987~.
The physiological and especially the pathophysiological importance o~ leukotriene B4 is summarized in several more recent works: a) The Leukotrienes, Chemistry and Biology eds. L. WO
Chakrin, D. M. Bailey, Academic Press 1984. b) J. W. Gillard et al., Drugs of the Future 12, 453 (1987). c) B. Samuelsson iet al., Science 237, 1171 (1987). d) C. W. Parker, Drug Development Research 10, 277 (1987)~ It follows from the above that LTB4 is an important inflammation mediator for inflammatory diseases, in which leukocytes invade the affected tissue.
It is known from the LTB4 that it causes tha adhesion of leukocytes on the blood vessel wall. LTB4 is chemotactically effective, i.e., it triggers a directed migration of leukocytes in the direction of a gradient of increasing concentration.
Further, because of its chemotactic activity, it indirectly changes the vascular permeability, and a synergism with prostaglandin E2 is observed. LTB4 obviously plays a decisive role in inflammatory, allergic and immunological processes.
Leukotrienes and especially LTB4 are involved in skin diseases, which accompany inflammatory processes (increased vessel permeability and formation of edemas, cell infiltration), increased proliferation of skin cells and itching, such as, for example, in eczemas, erythemas, psoriasis, pruritus and acne.

2~2~.~2 Patholoyically increas2d leukotriene concentrations are involved either causally in the development of many dermatitides or there is a connection between the persistence of the dermatitides and the leukotrienes. Clearly increased leukotriene concentrations were measured, for example, in the skin of patients with psoriasis or atopic dermatitis. Further, leukotrienes and LTB4 especially are involved in arthritis, chronic lung di~eases (e.g., asthma), rhinitis and inflammatory intestinal diseases as well as reper~usion damages of various organs.
Antagonists against LTB4 receptors or inhibitors of those enzymes which are involved in the synthesis of the LTB4 should be effective as specific medications, especially against diseases which accompany inflammations and allergic reactions.
Besides therapeutic possibilities, which can be derivsd from counteracting o~ LTB4 action with LTB4 analogs, the use~ulness and potential use of leukotriene-B4 agonists for the treatment of fungus diseases of the skin was also able to be shown ~H.
Katayama, Prostaglandins 34, 797 (1988~).
The invention relates to leukotriene-B4 derivatives of formula I

I_~\/R 1 (CH )m ¦
2 ~A B-D-R~, (I), ~R3 in which R1 means CH20H, CH3, CF3, COORs, CoNR6R7~ or R1 together with R2 means a carbonyl group, ~ 5 ~ ~122~2 ': ' R2 and R3, the same or different, represent H or an organic acid radical with 1-15 c atoms, R~ symbolizes H, C1-C14 alkyl, optionally substituted once or - several timesl C3-C10 cycloalkyl, C6-C10 aryl radical optionally substituted, independent from one another, once or several times :~ by halogen, phenyl, C1-C4 alkyl, C1~C4 alkoxy, fluoromethyl, chloromethyl, trifluoromethyl, carboxyl or hydroxy, or a 5-6 membered aromatic heterocyclic ring with at least 1 heteroatom, -;~ R5 means hydrogen, C1-C10 alkyl, C3-C1~ cycloalkyl, C6-C10 aryl `. radical optionally substituted by 1-3 halogen, phenyl, C1-C4 alkyl, Cl-C4 alkoxy, fluoromethyl, chloromethyl, trifluoromethyl, -~ carboxyl or hydroxy, CH2-CO-(C6-C10) aryl or a 5-6 membered ring with at least 1 heteroatom, A symbolizes a trans, trans-CH=CH~CH=CH, a -CH2CH2-CH=CH- or a tetramethylene group, ¦ B symbolizes a C1-C10 straight-chain or branched-chain alkylene group, which optionally can be substituted by fluorine . or the group -/ jCHz-, ( CH2 ) n D can mean a direct bond, oxygen, sulfur, -C_C-, -CH=CR8 or together with ..
B can also mean a direct bond, R6 and R7 are the same or different and represent H or c1-c4 . alkyl or R7 represents H and R6 represents C1-C15 alkanoyl or C1-C10 alkanesulfonyl, R8 means H, C1 -C5 alkyl, chlorine, bromine, ., ~, :~.
:
:

l~ - J~ 62:~22~

m symbolizes the numbers 1 or 4 and n is 3-5 as well as, if R5 means hydxogen, their salts with physiologically compatible bases and their cyclodextrin clathrates.
Groups ORZ and oR3 can be in ~- or ~-position. Formula I
comprises both racematas and the possible pure diastQreomers and enantiomers.
As alkyl groups R5, straight-chain or branched-chain alkyl groups with 1-10 C atoms are suitable, such as, ~or example, methyl, ethyl, propyl, butyl, isobutyl, tert butyl, pentyl, neopentyl, hexyl, heptyl, decyl. Alkyl groups R5 can optionally be substituted once to several times by halogen atoms, alkoxy groups, optionally substituted aryl or aroyl groups with 6-10 C
atoms (for possible substituents see under Aryl R5), dialkylamino and trialkylammonium with 1-4 C atoms in the alkyl part, and the single ~ubstitution is to be preferred. As substituents, there can b~ mentioned, for example, fluorine, chlorine or bromine, phenyl, dimethylamino, diethylamino, methoxy, ethoxy. As preferred alkyl groups R5, those with 1-4 C atoms are to be mentioned.
Cycloalkyl group R5 can contain 3-10, preferably 5 and 6 carbon atoms in the ring. The rings can be substituted by alkyl groups with 1-4 carbon atoms. For exampl~, there can be mentioned cyclopentyl, cyclohexyl, methylcyclohexyl.
As aryl groups R5, both substituted and unsubstituted aryl groups with 6-10 C atoms are suitable, such as, for example, phenyl, l-naphthyl and 2-naphthyl, each of which can be ~' 7 2~22~2 substituted by 1-3 halogen atoms (F, Cl, Br), a phenyl group, 1-3 alkyl groups each with 1-4 C atoms, a chloromethyl, fluoromethyl, trifluoromethyl, carboxyl, hydroxy or alkoxy group with 1-4 C
atoms. Preferred substituent~ in 3- and 4-position on the phenyl ring are, for example, fluorine, ch]orine, alkoxy or trifluoromethyl, however, hydroxy in 4-position.
As heterocyclic groups Rs, 5- a~d 6-membered aromatic heterocycles are suitable, which contain at least 1 heteroatom, pre~erably nitrogen, oxygen or sul~ur. For example, there can be mentioned 2-~uryl, 2 thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, oxazolyl, thiazolyl, pyrimidinyl, pyridazinyl, pyrazinyl, 3 furyl, 3-thienyl, 2-tetrazolyl, i.a.
As acid radical R6, physiologically compatible acid radicals are suitable. Preferred acids are organic carboxylic acids and sulfonic acids with 1-15 carbon atoms, which belong to the aliphatic, cycloalipha~ic, aromatic, aromatic-aliphatic and heterocyclic saries. These acids can be saturated, unsaturated and~or multibasic and/or substituted in the usual way. As examples for the substituents, C14 alkyl, hydroxy, C14 alkoxy, oxo or amino groups or ~aloyen atoms (F, Cl, Br) can be mentioned. For example, the following carb~xylic acids can be mentioned: formic acid, acetic acid, propionic acid, butyric acid, isobutyric acid, valeric acid, isovaleric acid, caproic acid, enanthic acid, caprylic acid, pelargonic acid, capric acid, undecanoic acid, lauric acid, tridecanoic acid, myristic acid, pentadecanoic acid, trimethylacetic acid, diethylacetic acid, tert-butylacetic acid, cyclopropylacetic acid, cyclopentylacetic ' ~' ' 8 2 .~ 9 .9 2 acid, cyclohexylacetic acid, cyclopropanecarboxylic.acid, -. cyclohexanecarboxylic acid, phenylacetic acid, phenoxyacetic acid, methoxyacetic acid, ethoxyacetic acid, mono-, di and trichloroacetic acid, aminoacetic acid, diethylaminoacetic acid, piperidinoacetic acid, morpholinoacetic acid, lactic acid, succinic acid, adipic acid, benzoic acid, benzoic a~ids substituted with halogen ~F, Cl, Br) or tri~luoromethyl, hydroxy, ~ Cl-b alkoxy or carboxy groups, nicotinic acid, isonicotinic acid, Y furan-~-carboxylic acid, cyclopentylpropionic acid. As especially preferred acyl radicals and alkanesulfonyl radicals, those with up to 10 carbon atoms are suitable. As sulfonic acids, for example, methanesulfonic acid, ethanesul~onic acid, isopropanesulfonic acid, ~-chloroethanesulfonic acid, ~ butanesulfonic acid, cyclopentanesulfonic acid, j cyclohexanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic ! acid, p-chlorobenzenesulfonic acid, N,N-dimethylamino~ulfonic acid, N,N-diethylaminosulfonic acid, N,N-bis-(~-chloroethyl)-aminosul~onic acid, N,N-diisobutylaminosulfonic acid, N,N-. dibutylaminosulfonic acid, pyrrolidino, piperidino, piperazino, .¦ N-methylpiperazino, and morpholinosulfonic acid are suitable.
.¦ As alkyl yroups R4, straight-chain and branched-chain, :-l saturated and unsaturated alkyl radicals, preferably saturated, ~ with 1-14, especially 1-10 C atoms, are suitable, which ~l optionally can be substituted by optionally substituted phenyl ! (for substitution, see under Aryl R5~. For example, there can be mentioned methyl, ethyl, propyl, butyl, isobutyl, tert-butyl, pentyl, hexyl, heptyl, octyl, butenyl, isobutenyl, propenyl, .
.

-- 9 ~12~

pentenyl, benzyl, m- and p-chlorobenzyl groups. If alkyl groups are halogen-substitut~d, ~luorine, chlorine and bromine are suitable as halogens.
As examples for halogen-substituted alkyl groups R4, alkyls with terminal trifluoromethyl groups are suitable.
Cycloalkyl group R4 can contain 3-10, preferably 3-~ carbon atoms in the ring. The rings can be substituted by alkyl groups with 1-4 carbon atoms. For example, there can be mentioned cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methyl-cyclohexyl.
As substituted or unsubstituted aryl groups R4, for example, phenyl, 1-naphthyl and 2-naphthyl, which respectively can be substituted by 1-3 halogen atoms (Fl, Cl, Br), a phenyl group, 1-

3 alkyl groups with respectively 1-4 C atoms, a chloromethyl, fluoromethyl, trifluoromethyl, carboxyl, C~-C4 alkoxy or hydroxy group are suitabl~. The substitution in 3- and 4-position on the phenyl ring, for example, by fluorine, chlorine, alkoxy or trifluoromethyl or in 4-position by hydroxy is preferred.
As heterocyclic aromatic groups R4, 5- and 6-me~bered heterocycles are suitable which contain at least 1 heteroatom, preferably nitrogen, oxygen or sulfur. For example, there can be mentioned 2-furyl, 2-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, oxazolyl, thiazolyl, pyrimidinyl, pyridazinyl, pyrazinyl, 3-furyl, 3-thienyl, i.a.
As alkylene group B, straight-chain or branched-chain, saturated or unsaturated alkylene radicals, preferably saturated with 1-10, especially with 1-5 C atoms are suitable, which ' ,., 10 21229t32 optionally can be substituted by ~luorine atoms. For example, there can be mentioned: methylene, fluoromethylene, di~luoromethylene, ethylene, 1,2-propylene, ethyl ethylene, trimethylene, tetramethylene, pentamethylene, 1,2-di~luoroethylene, l-fluoroethylene, l-methyltetramethylene, 1-methyltrimethylene, l-methylene~ethylene, 1-methylenetetramethylene.
Alkylene ~roup B can further represent the group -C-CH2-, in which n e 3-5, preferably 4-5. (~H2) n As acid radicals ~2 and R3, physiologically compa~ible acid radicals are ~uitable. Preferred acids are organic carboxylic acids and sulfonic acids with 1-15 carbon atom~, which belong to the aliphatic, cyclo-aliphatic, aromatic, aromatic-aliphatic or heterocyclic series. These acids can be saturated, unsaturated and/or multibasic and/or substituted in the usual way. As examples for the substituents, Cl4 alkyl, hydroxy, Cl4 alkoxy, o~o or amino groups or halogen atoms (F, Cl, Br) can be mentioned.
For example, the following carboxylic acids can be mentioned: formic acid, acetic acid, propionic acid, butyric acid, isobutyric acid, valeric acid, isovaleric acid, caproic acid, enanthic acid, caprylic acid, pelargonic acid, capric acid, undecanoic acid, lauric acid, tridecanoic acid, myristic acid, pentadecanoic acid, trimethylacetic acid, diethylacetic acid, tert-butylacetic acid, cyclopentylacetic acid, cyclohexylacetic acid, cyclohexanecarboxylic acid, phenylacetic acid, phenoxyacetic acid, methoxyacetic acid, ethoxyacetic acid, mono-, ;~ S,',~"` ~'S~ S~

~ 122~2 di- and trichloroacetic acid, aminoacetic acid, diethylaminoac~tic acid~ piperidinoacetic acid, morpholinoacetic acid, lactic acid, succinic acid, adipic acid, benzoic acid, benzoic acids substituted with halogen (F, Cl, Br~, trifluoromethyl, hydroxy, C~,4 alkoxy or carboxy groups, nicotinic acid, isonicotinic acid, furan-2-carhoxylic acid, cyclopentylpropionic acid. As especially preferred acid radicals R2 and R3, acyl radicals with up to 10 carbon atoms are suitable.
Alkyl radicals R6 and R7 are straight-chain or branched alkyl radicals, especially straight-chain, such as, for example, methyl, ethyl, propyl, butyl, pentyl, hexyl, especially preferably methyl.
R8 as C15 alXyl means straight-chain or branched-chain alkyl radicals such as were already mentioned for R4 or R5. Preferred alkyl radicals R8 are methyl, ethyl, propyl and isopropyl.
Inorganic and organic bases are suitable ~or salt formation, as they are known to one skilled in the art for forming physiologically compatible salts. For example, thers can be mentioned alkali hydroxides, such as sodium hydroxide and potassium hydroxide, alXaline-earth hydroxides, such as calcium hydroxide, ammonia, amines, such as ethanolamine, diethanolamine, triethanolamine, N-methylglucamine, morpholine, tris-(hydroxymethyl)-methylamine, etc.
To achieve the cyclodextrin clathrates, the compounds of formula I with ~, ~ or y-cyclodextrin are reacted. The ~-cyclodextrin clathrates are preferred.

~ ~ 12 2~22.~2 Preferred compounds of this invention are compounds of formula I, in which the radicals have the following meaning:
R1 is CH20H, CoOR5 with Rs meaning a hydrogen atom, an alkyl radical with 1-10 C atoms, a cycloalkyl radical with 5-6 C atoms, a phenyl radical optionally substituted by 1-2 chlorine, bromine, phenyl, C14 alkyl, C14 alkoxy, chloromathyl, fluoromethyl, tri~luoromethyl, carboxy or hydro~y, A is a trans, trans-CH=CH-CH=C~- or tetramethylene group:
B i~ a ~traight-chain or branched-chain, saturated or unsaturated alkylene group with up to 10 G atoms, which optionally can be substituted by fluorine or the group -C\CH2-(CH2) nwith n = 3-5;
D is a direct bond, oxygen, sulfur, a -C=C- group or a -CH=CR8 group with R8 as hydrogen, C~ 5 alkyl, chlorine or bromine;
B and D together are a direct bond;
R2 and R3 are the same or different and mean hydrogen or an organic acid radical with 1-15 C atoms;
R1 and R2 together are a carbonyl group:
R4 is a hydrogen atom~ C110 alkyl, cycloalkyl with 5-6 C
atoms, a phenyl radical optionally substituted by 1-2 chlorine, bromine, phenyl, Cl4 alkyl, C14 alkoxy, chloromethyl, fluoromethyl, trifluoromethyl, carboxy or hydroxy and if R5 means a hydrogen atom, their salts with physiologically compatible bases and their cyclodextrin clathrates.

' ' 13 ~22.~2 , Especially preferred compounds of this invention are compounds of formula I, in which the radicals have the following meaning:
is CH20H, CooR5 with R5 meani.ng a hydrogen atom, an alkyl radical with 1-4 C atoms;
R2 and R3 are the same or different and mean hydrogen or an organic acid radical with 1-6 C ato:ms;
¦ R1 and R2 together are a carbonyl group;
R4 is a hydrogen atom or Cl10-alkyl ' A is a trans, trans CH=CH-CH=CH~ or tetramethylene group;
~ B is a straight-chain or branched-chain alkylene group with Ji Up to 5 C atoms;
`! D is a direct bond or a -C_C- group or a -CH=CR8 group with R8 as hydrogen or C~ 5 alkyl;
B and D together are a direct bond;
¦ and i~ Rs means a hydrogen atom, their salts with i physiologically compatible bases and their cyclodextrin ¦ clathrates.
¦ The invention further relates to a process for the production of compounds of formula I according to the invention, 1 which is characterized in that an aldehyde of formula II
.1 ~C~o 2 ~L~ A y B- D- R ~, :
;~

21229.~

., .
in which m, A, B, D, ~3 and R4 have the above-indicated meanings, optionally after protection of free hydroxy groups with a magnesium-organic compound of formula II~, X Mg CH2 CH2 CH2 CH2 R (III~, in which X represents chlorine, bromine or iodine and R9 represents -CH3, CF3 or CH20Rl, in which R10 means an easily cleavable ether radical, is reacted and optionally then i~omers are separated in any seguence, protected hydro~y groups are released and/or a free hydroxy group is asterified and/or the 1-hydroxy group is oxidized to carboxylic acid and/or double bonds ar~ hydrogenated and/or an esterified carboxyl group ~Rl = CooR5) is saponified and/or reduced and/or a carboxyl group (R5 = H) is esterified and/or a free carboxy group (R5 = H) is convertad to an amide (Rl = CoNHR~R7) or a carboxyl group with a physiologically compatible base is converted to a salt.
As ether radicals R9 in the compound of formula III~ the radicals familiar to one skilled in the art are suitable. Easily cleavable ether radicals, such as, for example, dimethyl-tert-butylsilyl, trimethylsilyl, tribenzylsilyl, diphenyl-tert-butylsilyl, tetrahydropyranyl, tetrahydrofuranyl and ~-ethoxyethyl, to name only a few~ are preferable.
The reaction of the compound of formula II with an organometallic compound of formula III takes place in a way known in the art in an inert solvent or solvent mixture, such as, for example, dioxane, toluene, dimethoxyethane, or preferably diethyl ether or tetrahydrofuran. The reaction is performed at temperatures between -100C and 60C, preferably at -78C to 0C.

~

' ~' 15 ~1~2~

.
The production of the compou~d of formula III necessary ~or this reaction takes place by reactivn of the corresponding hydroxy halide protected by an easily cleavable ether group and subsequent reaction with magnesium.
The reduction to the compounds of formula I with Rl meaning a CH20H group is perf~rmed with a reducing agent suitable for the reduction of esters or carboxylic ac:ids, ~uch as, for example, lithiu~ aluminum hydride, ~iisobutyl alumin~m hydride, etc. As solvent, diethyl ether, tetrahydrofuran, dimethoxyethane, toluene, etc., are suitable. The reduction is performed at temperatures of -30C up to boiling temperature o~ the solvent used, preferably 0C to 30C.
The esterification of the alcohols of formula I (R2 = H
and/or R3 = H) takes place in a way known in the art. For example, the esterification takes place in that an acid derivative, preferably an acid halide or acid anhydride, is reacted in the presence of a base, such as, for example, NaH, pyridine, triethylamine, tributylamine or 4-dimethylaminopryidine with an alcohol of formula I. The reaction can be performed without solvent or in an inert solvent, preferably acetone, acetonitrile, dimethylacetamide, DMS0 at temperatures above or below room temperature, for example, between -80C to 100C, preferably at room temperature.
The oxidation of the l-hydroxy group is performed according to the methods known to one skilled in the art. As oxidizing agents, for example, there can be used: pyridinium dichromate (Tetrahedron ~etters, 1979, 399), Jones reagent (J. Chem. Soc.

~12~992 ~ ^ 16 '~ ' ' 1953, 2555) or platinum/oxygen (Adv. in Carbohydrate Chem. 17, ,, 169 (1962)) or Collins oxidation (Tetrahedron Letters 1968, 3363), and subsequent Jones oxidation. The oxidation with pyridinium dichromate is performed at temperatures of 0C to ~`~ 100C, preferably 20C to 40C in a solvent inert toward the i oxidizing agent, for example, dîmethylformamide.
The oxidation with Jones reagent is performed at temperatures of -~0C to +~0C, pre~erably 0C to 30C in acetone as solvent.
The oxidation with platinum/oxygen is performed at . temperatures of 0C to 60C, preferably 20C to 40C in a solvent i inert toward the oxidizing agent, such as, e.g., ethyl acetate.
The saponification of the esters of formula I is performed accordins to the methods known to one skilled in the art, such as, for example, with basic catalysts. The compounds o~ formula I can be separated by the usual separating method~ into the optical isomers.
The release of the functionally modifiad hydroxy groups takes place according to known methods. For example, the cleavage of hydroxy protecting groups, such as, for example, the tetrahydropyranyl radical, is performed in an aqueous solution of an organic acid, such as, e.g., oxalic acid, acetic acid, propionic acid, i.a., or in an aqueous solution of an inorganic acid, such as, e.y., hydrochloric acid. To improve the solubility, a water-miscible, inert organic solvent is suitably added. Suitable organic solvents are, e.g., alcohols, such as methanol and ethanol, and ethers, such as dimethoxyethane, :

~' 1 7 2:L2,7~9.~

dioxane and tetrahydrofuran. Tetrahydro~uran is pre~erably used.
The cleavage is performed preferably at temperatures b~tween 20C
and 80C. The cleavage of the silyl ether protecting groups takes place, ~or example, with tetr2lbutylammonium ~luoride or with potassium fluoride in the presence of a crown ether. As solvent, for example, tetrahydrofuraln, diethyl ether, dioxane, ! methylene chloride, etc., are suitable. The cleavage is performed preferably at temperatures between 0C and 80C.
The saponi~ication of the acyl groups takes place, for exampl~, with alkali or alkaline-earth carbonates or hydroxides ', in an alcohol or in the aqueous solution of an alcohol. As an i alcohol, aliphatic alcohols are suitable, such as, e.g., methanol, ethanol, butanol, etc., preferably methanol. As alkali ¦ carbonates and hydroxides, potassium salts and sodium salts can be mentioned. The potassium salts are preferred.
As alkaline-earth carbonates and hydroxides, for example, calcium carbonate, calcium hydroxide and barium carbonate are suitable. The reaction takes place at -10C to +70C, preferably at t2~C.
¦ The introduction of ester group -CooR5 for R1, in which Rs represents an alkyl group with 1-10 C atoms, takes place according to th~ methods known to one skilled in the art. The l-carboxy compounds are reacted, for example, with diazohydrocarbons in a way known in the art. The esterification with diazohydrocarbons takes placeJ e.g., in that a solution of the diazohydrocarbon in an inert solvent, preferably in diethyl ether, is mixed with the 1-carboxy compound in the same or in , ~ 18 21 22~2 another inert solvent, such as, e.g., methylene chlorideO After completion of the reaction in 1 to 30 minutes, the solvent is removed and thP ester is purified in the usual way. Diazoalkanes are either known or can be produced according to known methods torg. Reactions Vol. 8, pages 38~-394 (1954)].
The introduction of ester grou]p coo~5 for Rl, in which R5 represents a substituted or unsubstituted aryl group, takes place according to the methods known to one skill~d in the art. For example, the l-carboxy compounds with the corresponding arylhydroxy compounds are reacted in an iner~ solvent with ¦ dicyclohPxylcarbodiimide in the presence of a suitable base, for I example, pyridine, DMAP, triethylamine. As solvent, methylene i chloride, ethylene chloride, chloroform, ethyl acetate, tetrahydrofuran, preferably chloroform, are suitable. The raaction is performed at temperatures between -30C and ~50C, preferably at 10C.
If C=C double bonds contained in the primary product are to be reduced, the hydrogenation takes place according to methods known in the art.
The hydrogenation of ths ~8~10 diene system is performed in a way known in the art at low temperatures, preferably at about -20C to +30C in a hydrogen atmosphere in the presence of a noble metal catalyst. As catalyst, for example, 10% palladium on carbon is suitable.
The leukotriene-B4 derivatives of formula I with R5 meaning a hydrogen atom can be converted to a salt with suitable amounts of the corresponding inorganic bases with neutralization. For 19 2122~9~
.

example, during dissolving of the corresponding acids in water, which contains the stoichiometric amount o~ the base, the solid inorganic salt is obtained after evaporation of the water or : after addition of a water-miscible ~olvent9 e.g., alcohol or acetone.
For the production o~ an amine salt, the LTB4 acid, a.g., is dissolved in a suitable solvent, for example, ethanol, acetone, : diethyl ether, acetonitrile or benzene and at least the stoichiometric amount o~ the amine is added to thi~ ~olution. In i this way, the salt usually accumulates in solid form or is isolated after evaporation of the solvent in the usual way.
`~ The introduction of amide group -CONHR6 with R6 ~eaning alkanoyl takes place according to the methods known to one skilled in the art. The carboxylic acids of formula I (F~=H) arP
~ first converted to the mixed anhydride in the presence o~ a 3 tertiary amine, such as, for example, triethylamine, with chloroformic acid isobutyl ester. The reaction of the ~ixed anhydride with the alkali salt of the corresponding amide or with ¦ ammonia tR6=H) takes place in an inert solvent or solvent ¦ mixture, such as, for example, tetrahydrofuran, dimethoxyethane, dimethylformamide, hexamethylphosphoric acid triamide, at temperatures between -30C and +60C, preferably at 0C to 30C.
Another possibility for the introduction of amid~ group -CONHR6 consists in the reaction of a l-carboxylic acid of fo~mula I (~=H), in which free hydroxy groups are optionally intermediately protected, with compounds of formula IV, 0 = C = N - R6 (IV), .
., in which R6 has the above-indicated meaning.
The reaction of the compound oE formula I (~=H) with an isocyanate of formula IV takes place optionally by adding a tertiary amine, such as, e.g., triethylamine or pyridine. The reaction can be performed without solvent or in an inert solvent, preferably acetonitrile, tetrahydro~Euran, acetone, dimethylacetamide, methylene chloride, diethyl ether, toluenel at temperatures between 80C to 100C, pre~erably at 0C to 30C.
For production of the other amides, for example, the desired acid anhydrides can be reacted with ammonia or the corresponding amines.
If the initial product contains OH groups in the leukotriene-B4 radical, these OH groups are also reacted. If finally end products are desired which contain free hydroxyl groups, a start is suitably made from initial products in which the latter are intermediately protected by preferably easily cleavable ether or acyl radicals.
The separation of enantiomers and/or diastereomers takes place according to the methods known to one skilled in the art, for example, high-pressure liquid chro~atography on optically active vehicles.
The compounds of formula II with m meaning 1 being used as initial material can be produced, for example, by cis- or trans-bis-1,2-hydroxymethyl-cyclobutane (obtainable by reduction from cis- or trans-cyclobutane-1,2-dicarboxylic acid, see, e.g., analogously to A. Padwa et al., J. Org. Chem. 54, 817 ~1989); O.
Caamaus et al., Eur. J. Med. Chem. 22, 311 (1987) J.B. Jones et 2~22~92 ! . , 21 , '~ ' al., J. A. Chem. Soc., 104, 4659 (1982)) being converted in a way known in the art to the monosilylether of fo~mula Va I l r ~ 13 ~Va), .L,~_~ O H

~,~ in which , R12 and R15 are the sa~e or different and mean C1-C4 alkyl ¦ or phenyl.
~y oxidation, e.g., with Collins reagent or by the Swern ¦ process (Tetrahedron Letters 34, 1651 (1978)), there is obtained the aldehyde of formula VIa ¢ Osi - R12 ~VIa), CHO

(VIIa) or Et . (VIIIa), ~ EtO ~ 2p-cH2cH-cH-cooEt which is converted in a Wittig-Horner olefination with the phosphonate of formula VIIa and a base and optionally subsequent hydrogenation as well as subsequent reduction of the ester group, ''' ' 22 ~2~ 2 .

oxidation of the primary alcohol, repeated Wittig-Horner olefination with the phosphonate of formula VIIa and optionally subseguent hydrogenation to the ester of formula IXa or in a Wittig-~orner reaction of the aldehyde of formula VI with a phosphate of formula VIIIa, in which A

~ R11 OSi-- R12 (IXa), ~ /COOEt has the above-indicated meaning. As bases, for example, potassium-tert-butylate, diazabicyclononane, diazabicycloundecane, or sodium hydride are suitableO Reduction of the ester group, for example with diisobutyl aluminum hydride and subsequent oxidation of the obtained primary alcohol, e.y., with manganese dioxide or Collins reagent results in the aldehyde of formula Xa R ~1 051-- R ~ 2 ~Xa), , CHO
The organometallic reaction of the aldehyde of formula X ..
with a Grignard reagent of formula XIa, X-Mg-B-D-R4 (XIa), in which B, D and R4 exhibit the above-indicated meanings and X
means chlorine, bromine or iodine, results, after protection of the hydroxy group (for example~ by acylation) and optionally diastereomer separation in the compounds of formula XIIa 23 2~2~99~
,.~ .

OSi-- R12 I--~ \ R13 - ~ A y s-D-n~ (XIIa), The pro~uction of the compound o~ ~ormula XIa necessary for the organometallic reaction takes p].ace by reaction o~ the corrPsponding terminal halide with magne~ium. By reaction o~
silylether XIIa with tetrabutylammonium fluoride and optionally diastereomer separation, the alcohol of formula XIIIa is obtained. ~ - OH

11A -D-R~ (XIIIa), The oxidation of the primary alcohol group in XIII, e.g., Collin~ reagent or pyridinium dichromate, results in the aldehyde of formula II.
Ths compounds of formula XII, in which B means a CH2 group and D means a CH=CR8 group, can be achieved, for example, by an organometallic reaction of a propargyl halide and subsequent alkylation with a corresponding alkyl halide and optionally subsequent Lindlar hydrogenation.
An alternative design of the lower chain starts from the aldehyd~ of formula XIVa, which resulted from the Wittig-Horner reaction of aldehyde VI and subsequent reduction and oxidationO

si ~ R12 (XIVa), ~,~ R13 ~HO

' 2~ 2~2299~
,-~

Wittig-Horner olefination o~ aldehyde XIII with a phosphonate of formula XVa ~ o o :~ 11 11 (CH30)2PCH2-C-~-D-R~ (XVa), and reduction of the resulting ketone then resulted in the I alcohol of formula XIIIa that can be saparated in the ,~. dias~cexeomersO
i The separation of enantiomers and/or diastereomers takes place according to the methods known to one skilled in the art, ~ fur example, high-pressure liquid chromatography on optically ¦ active vehicles.
he compounds of formula II with m meaning 4 being used as initial material can be produced, for example, by an ester o~
cis- or trans-bis-1,2-dicarboxylic acid-cycloheptane (known by ;¦ example from G. Sicher et al., Collection Czechoslov. Chem.
Co~mun. 24, 262 (1961)3 being converted in a way known in the ark by xeduction to the diol of formula Vb \f~--OH
(Vb), \_/ ~--O H

The diol of formula Vb can then be subsequently converted according to known mathods into the monosilyl ether of formula VIb .
.

.1 2 ~22992 , R
\~S~ 2 ~OH (Vlb), in which R1l, R12 and R13 are the same or different and mean C1~C4-alkyl or phenyl~
By oxidation, e~g~, with Collins reagent or by the Swern ,, process (Tetrahedron Letters 34, 1651 ~1978~), there is obtained ¦ the aldehyde of formula VIIb R 11 < / ~ \ Rl3 (VIIb), - CHO

(VIIIb) or i EtO ) 2PCH2CO2Et IXb), , ~EtO)2P-CH2CH=CH-COOEt ¦ which is converted in a Wittig-Horner olefination with the phosphonate of formula VIII and a base and optionally subsequent hydrogenation as well as subsequent reduction of the ester group, oxidation of the primary alcohol, again Wittig-Horner olefination ~ '. 2~
2 ~ 9 2 with the phosphonate of formula VIII and optionally subseguent hydrogenation in tha ester o~ ~ormula Xb ~ COOEt A ( X b ), or in a Wittig-~orner reaction of the aldehyde of ~ormula VIIb with a phosphonate of formula IXb, (in this way a cis/trans-isomerization in the ring system can partially take place, and the isomers are separable in later stages), in which A
has the above-indicated meaning. As bases, for example, potassium-tert-butylate, diazabicycloundecane, dia~abicyclononane or sodium hydride are suitable. Reduction of the est~r group, for example with diisobutyl aluminum hydride and subsequent oxidation of the obtained primary alcohol, e.g., with manganese dioxide or Collins reagent results in the aldehyde of formula XIb ~\f~ \ R 13 ~A~ C~ ~Ib), `~

The organometallic reaction o~ the aldehyde of formula XI

with a Grignard reagent of formula XIIb, X-Mg-B-D-R4 (XIIb3, ~1 ~ 7 2~22992 `
in which B, D and R4 e~hibit the ahove-indicated meanings and X
means chlorine, bromine or iodine, results, after protection of the hydroxy group and optionally diastereomer separation (for example, by acylation3 in the compounds of formula XIIIb ~ ~ .

o s i-- R I

Ay 8-D-R4 (XIIIb), o R3 The production of the compound of formula XIIb necessary for ~¦ the organometallic reaction takes place by reaction of ths .~ corresponding terminal halide with magnesium. By reaction of silylether XIIIb with tetrabutylammonium fluoride and optionally diastereomer separation, the alcohol of formula XIVb is obtained.

\~ - O H

~/I A ~ B ,, tXIVb), The oxidation of the primary alcohol group in XIVb, e.g., Collins reagent or pyridinium dichromate, results in the aldehyde of formula II.

:

.1, 28 21 22.~92 . .
The compounds of formula XIII, in which B means a CH2 group and D means a CH=CR~ yroup, can be achieved, for example, by an organometallic reaction of a propargyl halide and subsequent alkylation with a corresponding alkyl halide and optionally subsequent Lindlar hydrogenation.
An alternative design of the lower chain starts from the aldehyde of formula XV~ which resulted from the Wittig-Horner reaction of aldehyde VIIb and subse~uent reduction and oxidationO

i' R 1 1 05i-- R

~/~ CH0 Wittig-~orner olefination of aldehyde XV with a phosphonate I of formula XVIb . O o . 11 11 lcH3o)2pcHz-c-B-D-R~ (XVIb), and reduction of the resulting ketone then resulted in the alcohol of formula XIIIb that can be separated in the ! diastereomers.
i The incorporation of the chemically and metabolically labile ! CiS-~6~7 double bond of the LTB~ in a cis- or trans-1,2-substituted cycloheptyl ring results in a stabilization, and especially by further derivatizing of the functional groups, LTB4 derivatives are obtained which can act as LTB4 antagonists.

I
i 1 , , , , 29 2 1~2992 The compounds o~ formula I act in an antiinflammatory and antiallergic manner. In addition, they have antimycotic i proper~-ies. Consequently, the new leukotriene-B4 derivatives o~
- formula I represent valuable pharmaceutical active ingredients.
`I The compounds of formula I are espe,cially suitable for topical ~ a~ministration, since ~hey ex~libit ia di~sociation between desired `' topical ~ffectiveness and undesirable systemic side effects.
The new leukotriene-B4 derivatives o~ formul~ I are suitable I in combination with the auxiliary agents and vehicles usual in galenic pharmaceutics for topical treatment of contact dermatitis, eczemas of the most varied types, neurodermatoses, erythrodermia, pruritus vulvae et ani, rosacea, lupus erythematosus cutaneus, psoriasis, lichen ruber planus et verrucosis and similar skin diseases.
¦ The production of the pharmaceutical agent specialties takes ¦ place in the usual way by the active ingredients ~eing converted ~ with suitable additives to the desired form o~ administxation, ; such as, for example: solutions, lotions, ointments, creams or plasters.

i In the thus formulated pharmaceutical agents, the active ingredient concentration depends on the ~orm of administration~
In lotions and ointments, an active ingredient concentration of ¦ 0.0001% to 1% is preferably used.
~¦ Further, the new compounds optionally in combination with the usual auxiliary agents and vehicles are also well-suited for the production of inhalants, which can be used to treat allergic -:

2 1 2 ~ 9 ~2 diseases of the respiratory system, such as, for example, bronchial asthma or rhinitis.
Further, the new leukotriene-~ derivatives are also suitable in the form of capsules, tablets or coated tablets, vhich pre~erably contain 0.1 to 100 mg of active ingredient or are administered orally or in the form of ~uspensions, which preferably contain 1-200 mg of active ingredient per dosage unit, and are also administered rectally to treat allergic dlseases of the intestinal tract, such as colitis ulcerosa and colitis granulomatosa.
The new leukotriene-B4 derivatives can also be used in combination, such as, e.g., with lipoxygenase inhibitors, cyclooxygenase inhibitors, prostacyclin agonists, thromboxane antagonists, leukotriene-~ antagonists, leukotriene-E4 antagonists, leukotriene-F4 antagonists, phosphodiesterase inhibitors, calcium antagonists or PAF antagonists.
The following embodiments are used to explain the process according to the invention in more detail. In the examples, diastereoisomers in 5-position not characterized in more detail were characterized as ~olar or nonpolar (e.g., diastereomer nnPOlar (5)).

31 2~2~92 13:~lPLE 1 ~ 5R8)-5-A~eto~y-5-~oi~2R83-2~ ,3~3 ~5~ 5-a~ato~y-1~3 trideoadie~yl~(lRS~-~y~lobutyl~-pe~tanoic a~id diastereom~r polar ~5) A solution of 8.9 g of 4-chloro-1-(tert.-butyldimethylsilyloxy~-butan in 8 ml of tetrahydrofuran is instilled in 1.92 g of magnesi~m at 25C under argon, a crystal of iodine is added, it is heated for 10 minutes to 70C, stirred for 30 minutes at 25C and diluted with 25 ml o~ tetrahydrofuran.
A solution of 4.8 g of cis-(lRS)-l-formyl-(2RS)-2[(1E,3E)-(5RS)-5-acetoxy-1,3-tridecadienyl]-cyclobutane in 40 ml of tetrahydro~uran is instilled in 30 ml o~ this magnesium-organic solution at -70C under argon and stirred for 0.5 hours at -70C.
It is mixed with 50 ml of saturated ammonium chloride solution, extracted three times with diethylether, the organic phase is shaken with semiconcentrated a~ueous sodium chloride solution, dried on anhydrous sodium sulfate and concentrated by evaporation in a vacuum. The residue is chromatographed on silica gel. With hexane/ethyl acetata (8+2), 3 diastereomeric 5-(tert.-butyldimethylsilyloxy)-1-cis{2-[~(lE,3E)-(5RS)-5-acetoxy-1,3-tridecadienyl]-cyclobutyl}-pentan-1-ol diastereomers are obtained in the sequence of increasing polarities.
0.7 g diastereomer nonpolar(5), A
0.6 g diastereomer nonpolar~5), B
3.6 g diastereomer polar(5) IR(CNCl3): 3580, 2930, 2860, 1728, 1252, 995, 838 cm~1.

32 21~2~2 For acetylation, 4.5 ml of acetic anhydride is-added to a solution of 3.5 g of the above-described alcohol indicated as (polar(5) diastereomer) in g ml of pyridine and stirred for 23 hours at room temperature. Then it is concentrated by evaporation in a vacuum while adding toluenP and the residuP is chromatographed on silica g~l. With hexane/diethyl ether (8~2~, 3.7 g of the correspo~ding acetate is obtained as colorless oil.
IR: 2930, 2862, 1728, 1610, 1375, 1254, 993, 839 ~m~1.
For silylether cleavage, 3.67 g of the ahove-produced acetate in 130 ml of tetrahydrofuran is stirred with 3.67 g of tetrabutylammonium fluoride for 30 minutes at oC and for 3 hours at 24C under argon. Then, it is diluted with diethylether, washed three times with water, dried on anhydrous magnesium sulfate and concentrated by evaporation in a vacuum. The residue ig chromatographed with diethylether on silica gel. In this way, , 2.84 mg of (+/-)-(5RS)-5-acetoxy-5-[cis-(2RS)-2-((lE,3E)-(5RS)-5-i acetoxy-1,3-tridecadienyl)-~lRS)-cyclobutyl]-pentan-1-ol is obtained as colorless oil.
IR: 3600 (broad), 2930, 28~0, 17~, 1610, ~370, 1250, 990 c~~1.
For oxidation of the 1-hydroxy group, 16.4 g of Collins reagent (bis-pyridine-chromium(VI)-oxide complex; Tetrahedron Letters 1968, 3363) is added to 2.76 g of the above-produced ~i alcohol in 150 ml of dichloromethane at O~C and stirred for 20 minutes at 0C. Then, it is diluted with a mixture of hexane/diethyl ether (1+1), Celite is added, filte~ed, washed with hexane/diethyl ether (1~1) and concentrated by evaporation I

33 212~9~

in a vacuum. The thus obtained l-aldehyde is immediately further processed without furthar purification.
5.3 ml of Jones reagent (chromium(VI)-oxide in H2SO4~ (J.
Chem. Soc. 1953, 2555) is instilled in a solution of 2.47 g of the thus produced aldehyde in 50 ml o~ acetone with stirring at -25C and stirred for 15 minutes at -25C under argon. Then, 3 ml of 2-propanol is added, stirred for 5 minutes, diluted with 250 ml of di~thyl ether, shaken twice with semiconcentrated agueous sodium chloride solution, dried on anhydrous magnesium sulfate and concentrated by evaporation in a vacuum. The xesidue is chromatographed on silica gel. With hexane~diethyl ether (1~1), 1.96 g of the title compound is obtained as colorless oil.
IR: 3520 (broad), 2930, 2860, 1728, 1375, 1250, 990, 948 cm~~.
The initial material for the above title compound is produced as follows:
la) 3-[cis-1-(tert.-Butyl-dimethylsilyloxymethyl)-cyclo-but-2-yl]-(2~)-propenoic acid ethyl ester 46 ml of a 1.2 molar solution of diisobutylaluminum hydride in toluene is instilled in a solution of 2.8 g of 2-hydroxymethyl-cyclobutanecarboxylic acid lactone ~C.C. Schroff et al., J. Org. Chem. 36, 3356 (1971)~ in 70 ml of toluene at 0C
under argon and stirred for 50 minutes at 0C. Then, 20 ml of 2-propanol and 23 ml of water are instilled, stirred for 2 hours at 22C, filtered, washed with dichloromethane and concentrated by evaporation in a vacuum. Tha residue is purified by chromatography on silica gel. With ethyl acetate/hexane ~4~1), 34 2122~

2.1 g of cis-1,2~dihydroxymethyl-cyclopentane is obtained as colorless liquid.
IR: 3600, 3400, 2960, 1060 cm~1.
A solution of 7.8 g of the above-produced diol in 12 ml of tetrahydrofuran is instilled in a sllspension of 2.93 g of sodium hydride (as a 55% suspension in mineral oil) in 130 ml o~
tetrahydrofuran at 22C and stirred ~or 4S minutes at 22C.
Then, 10 g of tert.-butyldimethylsilyl chloride is added, stirred for ~5 minutes at 22C and then diluted with about 0.8 liters of diethyl ether. The ether extract is wa~hed with 10% aqueous potassium carbonate solution, shaken three times with water, dried with anhydrous sodium sulfate and concentrated by evaporation in a vacuum. The residue is chromatographed on silica gel. With hexane/diethyl ether (95~5), 16.9 g of cis-l-tert.-butyl-dimethylsilyloxymethyl)-2-hydroxymethyl-cyclobutane is obtained as colorles~ liquid.
IR: 3420 (broad), 2960, 2863, 1260, 840 cm~1.
70 g of Collins reagent (chromic acid-pyridine complex) is added to a solution of 9 g of the above-described monoæilylether in 450 ml of dichloromethane at 0C and stirred for 30 minutes at 0C. Then, it is diluted with a mixture of hexanefdiethyl ether (3+2), Celite is added, filtered and concentrated by evaporation in a vacuum. 8.7 g of the aldehyde is obtained which is used without further purification.
IR: 2958, 2930, 2860, 2740, 1713, 840 cm~1.
For the Wittig olefination, 12 g of phosphonoacetic acid triPthyl ester and 7.2 g of diazabicycloundecene (DBU) are added ~` ~5 2~22992 at 24C to a stirred suspension of 2.3 g of lithium chloride in 150 ml oE acetonitrile and stirred for 15 minutes. Then, a solution of 8.7 g of the above-described aldehyde in 24 ml of acetonitrile is instilled, stirred for 2.5 hours at 24C and then diluted wit~ diethyl eth2r. It is shaken in succession with water, 10% agueous ~ulfuric acid and water, dried with a~hydrous sodium s~lfate and concentrated by evaporation in a va~uum. The residue is chromatographed with hexane~diethyl ether (95+5) on sili~a gel. In this way, 9.0 g of the title ¢ompound is obtained as colorless oil.
IR: 2950, 2860, 1710, 1650, 1260, 993, B40 cm~1.

lb) 5-[cis-1-(tert.-butyl-dimethylsilyloxymethyl)-cyclo-but-2 yl~-(2E,4E)pentadienoic acid ethyl ester 129 ml of a 1.2 molar solution of diisobutylaluminum hydride in toluene is instilled in a solution of 21 g of the ~
unsaturated ester, produced according to example la, in 250 ml of toluene at -70C under argon and stirred for 30 minutes at -70C.
Then, 30 ml of 2-propanol and then 60 ml of water are instilled, stirred for 2 hours at 22C, filtered, washed with dichloromethane and concentrated by ~vaporation in a vacuum.
18.1 g of 3-[cis-1-(tert.butyldimethylsilyloxy-methyl)-cyclo-but-2-yl]-(2E)-2-propen-1-ol is obtained, which is used without further purification.
IR: 3600, 3400, 2058, 840 cm~l.
A solution of 18 g of the above-produced alcohol in 400 ml of toluene is mixed with 61 g of manganese dioxide and stirred ., i I

2~22~92 -~ 36 for 5 hours at 24C. Then, it is filt~red, concentrat~d by evaporation and chromatographad on silica ~elO With hexane/diethyl ether (92+8), 17.6 g of the aldehyde is eluted as colorless oil.
IR: 2950, 28~0, 2740, 1680, 1~33, 1470, 975, 840 cm~1.
For Wittig olefination, 19.4 g of phosphonoacetic acid trieth~l ester and 11.7 g of diazab:icycloundecene are added at 24C to a stirred suspension of 3.66 g of lithium chloride in 255 ml of acetonitrile and stirred for 15 minutes. Then, a solution of 15~7 g of the above-described ~ unsaturated aldehyde in 40 ml of acetonitrile is instilled, stirred for 4 hours at 24C and then diluted with diethyl ether. It is shaken in succession with watex, 10% aqueous citric acid solution and water, dried with anhydrous sodium sulfate and concentrated by evaporation in a vacuum. The residue is chxom~tographed with hexane/diethyl ether ~9+1) on silica gel. In this way, 11.9 g of the title compound is obtained as colorless oil.
j IR: 2958, 2860, 1703, 1638, 1615, 1255, 1003, 970, 837 cm~1.

j lc) 5-tcis-1-(tert.-Butyl-dimethylsilyloxy~methyl~-cyclo-but-2-yl]-(2E,4E)-pentadien-1-ol 76 ml of a 1.2 molar solution of diisobutylaluminum hydride in toluene is instilled in a solution of 12 g of the ester, produced according to example lb, in 200 ml of toluene at -70C
under argon and stirred for 30 minutes at -70C. Then, 30 ml of 2-propanol and then 40 ml of water are instilled, stirred for 3 : 2122992 ~~ 37 hours at 23C, filtered, washed with dichloromethane and concentrated ~y evaporation in a vacuum. The residue is puri~ied ; by chromatography on silica gel. With hexane~diethyl eth~r (8+2~, 7.5 g of the alcohol is obtained as colorless oil.
- IR: 3620, 3460, 838 cm~l~
A solution of 703 g of the above-produced alcohol in 150 ml ~' o~ toluene is ~ixed ~ith 23.3 g of manganese dioxide and stirred ~or 6 hours at 24C. Then, it is filtered, concentrated by evaporation and chromatographed on silica gel. With hexane/diethyl ether (9+1~, 5.4 y o~ the title compound is obtained as colorless oil.
IR~ 2955, 2858, 2740, 1683, 1634, 991, 842 cm~l.
. ~

ld~ (5RS)-5-Acetoxy-1 [cis-l-(tert.-butyl-dimethylsilyloxymethyl~-cyclobut-2-yl3-(lE 3E)-tridecadiena A solution of 8.9 g of octyl bromide in 10 ml of die~hyl ¦ ether is instilled in 1.12 g of magnesium in 4 ml of diethyl i ether with heating and stirred for 30 minutes at 25C.
; A solution of 5.1 g of the aldehyde, produced according to example lc, in 60 ml of diethyl ether is instilled in 9.6 ~1 (=20.0 ~mol) of this Grignard solution at -20C under argon and stirred for 45 minutes at -20C. It is mixed with saturated aqueous ammonium chloride solution, extracted three times with ¦ diethyl ether, the organic phase is shaken with semiconcentrated aqueous sodium chloride solution, dried on anhydrous sodium sulfate and concentrated by evaporation in a vacuum. The residue is chromatographed on silica gel. With hexane/ethyl acetate, ~ ..

~ .' 2~2~992 _ 38 ., 7. n g of the corresponding alcohol is obtained as diastereomeric mixture.
For acetylation, 10 ml of acet:ic anhydride is added to a - solution of 60 96 g of the above-produced diastereomeric alcohol : mixture in 20 ml of pyridine and st:irred or 24 hours at room temperatureO Then, it is concentrated by evaporation in a vacuum ; while adding toluene and the residue is chromatographed on silica gel. With hexane/diethyl ether (95~5~, 7.5 g of the title compound (nonpolar diastereomer~ is obtained a~ colorless oil.
. IR: 2938, 2860, 1725, 1655, 1250, 990, 838 cm~1.
le) cis-(lRS)-l-Formyl-(2RS)-2-[(lE,3E)-(5RS)-5-acetoxy-1,3-tridecadienyl]-cyclobutane 10.83 g of tetrabutylammonium fluoride is added to a solution of 7.5 g of the acetate produced according to example ld, in 170 ml of tetrahydrofuran at 0C, stirred for 15 minutes at 0C and for ~.5 hours at 24C. Then, it is diluted with 1 liter of diethyl ether and washed three times with ~e~iconcentrated aqueous sodium chloride solution. It is dried on anhydrous magnesium sulfate, concentrat~d by evaporation in a vacuum and the residue is chromatographed on silica gel. With hexane/diethyl ether (7+3), 5.2 g of (5RS3-1-(cis-hydroxymethyl-cyclobut-2-yl)-(lE,3E)-tridecadiene is elutPd as colorless oil.
IR: 3610, 3450, 2930, 2860, 1726, 1250, 992 cm~1.
32 g of Colli:ns reagent (chromic acid-pyridine complex) is added to a solutio:n of 5.0 g of the above-produced alcohol in 140 ml of dichloromethane at 0C and stirred for 20 minutes at 0C.

```~1 `; , 2~22992 . ~ ~ 39 :
Then, it is diluted with a mixture o~ hexane/diethyl ether (l~
Celite is added, filtered and concenkrated by evaporation in a vacuum. The thus obtained aldehyde wa~ used without further purification. ~Crude yield 4.8 g).
~, IR: 2930, 2860, 2~30, 1721, 1250, 990 cm~.
', .
~a~pl~ 2 ~ 5~-5~y~ro~y-S-toi~-(2R~-2-~lB,3B)-$5R8)-S-hy~roxy-:3 l~3-trid~oaaie~yl)-~lR~)-cyclobutyl] penta~oio ~oi~
Di~t~reomer polar ~5)

4.5 ml of a 0.5 molar aqueous lithium hydroxide solution is added to a solution of 200 mg of the diacetate (diastereomer polar (5)), produced according to example l, in 4.5 ml o~
~ methanol and stirred for 25 hours at 50C. Then, ik is acidified ! with a 10% aqueous sulfuric acid to pH 5, diluted with ethyl acetate, shaken twice with semiconcentrated aqueous sodium chloride solution, dried with anhydrous sodium sulfate and ¦ concentrated by evaporation in a vacuum. The residue is ¦ chromatographed with diethyl ether/ethanol ~99+l~ on silica gel.
¦ In this way, 148 mg o~ the title compound is obtained as colorless oil.
IR: 3400, 2930, 2860, 1725, 1365, 1245, 992 cm~l.

`I

G~`' ~G ~ c~

2:~2~9~2 . ~o E~:ampl~ 3 ~ (5R8~5-Aceto~y-5-Eci~ g~2~ 5R~)-5 hy~ro~y-1,3~tri~ecadienyl)~1R~ iyclobutyl]-penta~oia ACi~
Diaitereom~r polar (5~
6.6 ml of a 0.5 normal agueous sodium hydroxide solution is added to a solution of 300 mg of the polar diastereomeric diacetate, produced according to example 1, in 6.6 ml o~ methanol at 23C and stirred for 0.75 hours at 23C under argon. Then, it is diluted with water and acidified at ice bath temperature with 10~ aqueous sulfuric acid to pH 5. It is extracted with ethyl acetate, washed twice with semiconcentrated aqueous sodium chloride solution, dried with anhydrous sodium sulfate and concentrated by evaporation in a vacuum. The residue is chromatographed on silica gel. With diethyl ether/h~xane (8~2), 202 mg o~ the title compound is obtained as colorless oil.
IR: 3600, 2925, 2858, 1729, 1712, 1700, 1250, 993, 960 cm-l.
`.,.
~xampl~ 4 (~ 5R8~-5-~ydroxy-5-[cis-(2R3)-2-((lB,3~-(5R8)-5-hy~roxy-1,3 tride¢aaie~yl~-llR~ yolobutyl3-pa~tan-~-ol ~ia~tereo~er polar i~5) 360 mg of the polar diastereomeric diacetate (diastereomer polar (5~) described in example 1 is stirred for 60 hours at 24C
with 11 ml of a solution of potassium hydroxide in water and ethanol (production: 5 g of potassium hydroxide is dissolved in 67.5 ml of water and 182.5 ml of ethanol~. Then, it is acidified r - 41 2:L229~2 .

with 10% aqueous citric acid ~olution to p~I 6, ex~racted ~our times with 20 ml of dichloromethane each, the organic phase is shaken with semiconcentrated sodium chloride solution, dried on anhydrous magnesium sulfate and concentrated by evaporation in a vacuum. The residue is chromatographed with ethyl acetate on silica gel. In this way, 103 mg of the title compound is obtained as colorless oil.
IR: 3605, 33S0 ~broad), 2930, 2860, 993 cm~1.
. .

~ampl~ 5 (~J-~-(5~8) 5-Aaeto~y;5 ~cis-(2R~ ,3E)-(5R8~-5-aceto~y-l 1,3-tri~eo~die~yl)-(lR~)-cyolobutyl3-pe~tanoio aoid J Diastereo~r no~polar ~5), ~
¦ For acetylation, 1 g of acetic anhydride is added to a I solution of 0.61 g of the above-described nonpolar alcohol¦ (diastereomer nonpolar (5), A) in 2.0 ml of pyridine and stirred for 22 hours at room temperature. Then, it is concentrated by evapo~ation in a vacuum while adding toluene and the residue is chromatographed on silica gel. With hexane/diethyl ether (9~1), 0.62 g o~ the acetate is obtained as colorless oil.
IR: 2930, 2860, 172S, 1606, 1374, 1252, 993, 840 cm~1.
¦ ~or silylether cleavage, 0.61 g of the above-producedacetate in 25 ml of tetrahydrofuran is stirred with 0.7 g of tetrabutylammonium fluoride for 20 minutes at 0C and for 4 hours at 24C under argon. Then, it is diluted with diethyl ether, washed three times with water, dried on anhydrous magnesium sulfate and concentrated by evaporation in a vacuum. The rasidue . 42 2~229~

is chromatographad with diethyl ether/hexane ~8~2~ on silica g~l.
In this way, 1.3 g of the l-alcohol is obtained as colorless oil.
IR: 3620, 3450, 2930, 2860, 1725, 1608, 1375, 1250, 990 cm-~.
For oxidation of the l-hydro~y group, 2.5 g of Collins reagent is added to 0.43 g of the ak~ove-produced alcohol in 50 ml of dichloromethane and stirred for 20 minutes at 0C. Then, it is diluted with a mixture of hexane/diethyl ether (1+1~, Celite is added, ~iltered, washed with hexane/diethyl ether (l~lj and concentrated by evaporation in a vacuum. The thus obtained ~-aldehyde is immediately processed further without further purification.
0.9 ml of Jones reagent (3. Chem. Soc. .1953, 2555) is instilled in a solution of 0.41 g of the above-produced aldehyde in 10 ml o~ acetone with stirring at -25C and stirred for 15 minutes at -25C under argon. Then, 2 ml of 2-propanol is added, stirred for 5 minutes, diluted with 60 ml o~ diethyl ether, shaken twice with semiconcentrated sodium chloride solution, dried on anhydrous sodium sulfate and concentrated by evaporation in a vacuum. The residue is chromatographed on silica gel. With die~hyl ether/hexane (7+3), 374 mg of the title compound is obtained as colorless oil.
IR: 3520 (broad), 2930, 2859, 1725, 1372, 1250, 99o cm~1.

The initial material for the above title compound is produced as follows:

:

. 43 2 12 ~9~2 ~xample 6 ~ (5R8)-5-~ydro~y-5-[cis-(2R~)-2-((lE,3E~-~5~8)-5-hyaroxy-1,3-tri~e~adienyl~-51~8~-cyolobutylJ-penta~oi~ aaid Dia~tereo~er no~polAr (5) ~
~nalogously to example 2, 124 mg of the title compound is obtained as colorl~ss oil from 180 mg of the diac tate, produced according to example 5.
IR: 3400, 2930, 2858, 1725, 1360, 1250, 992, 930 cm1.

. .
', ~xample 7 ~+/-~-t5R8)-5 Aoetoxy-5-lcis-~R~)-2~ 3~1-(5~s1-5-hydroxy 1,3-tridecadienyl) (lR~)-cyclobutyl]-penta~oic acid Z Diastereomer ~o~polar (5) A
j Analogously to example 3, 123 mg of the title compound is ¦ obtained as colorless oil from 150 mg of the diacetate, produced ¦ according to example 5.
! IR: 3600, 2930, 2860, 1721, 1252, 992, 962 cm~1.

B~ampla 8 (SR8)-5 ~ydroxy-5-tois-~2R8)-2-5~1Ej3B)-~5RS~-5 hydroxy-1,3-~ridecadienyl~-(lRS~-cyclobu~yl]-pe~ta~ ol ¦ Diastoreomer nonpolar ~5) A
Analogously to example 4, 95 g of the title compound is obtained as colorless oil from 170 mg of the diacetate produced according to example 5.
IR: 3600, 3380 (broad), 2930, 2860, 992 ~n1.

2122~2 E:~ampl~ 9 (+/~ 5~8~-5-Acetoxy-s-~tra~-~2~ 2~ ,3E)-(5R8)-5-a~eto~y-1~3-trl~eaa~ieayl3-(lR~-¢yclobutyl~-pentanoi~ aci~
Dia~tereomer B
A solution of 8.9 g of 4-chloro~ (tert.-butyldimethylsilyloxy3-butane in 8 m:L of tetrahydrofuran is instilled in 1.92 g of magnesium at ;25C under argon, a crystal of iodine is added, heated for 10 minutes to 60C, stirred for 30 minutes at 25C and diluted with 25 ml o~ tetrahydrofuran.
A solution of 4.0 g of trans-(lRS)-l-formyl-(2RS~-2-[(lE,3E)-(SRS)-5-acetoxy-1,3-tridecadienyl-cyclobutane in 40 ml of tetrahydrofuran is instilled in 25 ml of this magnesium-organic solution at -70C under argon and stirred for 0.5 hours at -70C. It is mixed with 100 ml of saturated aqueous ammonium chloride solution, extracted with diethyl ether, the organic phase is shaken with semiconcentrated aqueous sodium chloride solution, dried on anhydrous sodium sulfate and concentrated by evaporation in a vacuum. The residue is chromatographed on silica gel. With hexane/ethyl acetate (85+15), 2 5-(tert.-butyldimethylsilyloxy-l-trans-~2-[lE,3E-(5RS)-5-aceto~y-1,3-tridecandi~nyl3-cyclopentyl}-pentan-l-ol diastereomers in the sequence of increasing polarity.
1.94 g o~ nonpolar diastereomer A
1.7 g of polar diastereomer B
IR: 3430, 2932, 2859, 1725, 1372, 1256, 992, 839 cm~l.
For acetylation, 1.0 ml of ac~tic anhydride is added to a solution of 0.9 g of the above-produced alcohol (diastereomer B) ~229~2 in 20 ml of pyridin~ and stirred for 2~ hours at room temperature. Then, it is concentrated by evaporation in a vacuum while adding toluene and the residue is chromatographed on silica gel. With hexane~ethyl acetate (85-~15), 0.97 g of the acetate is obtained as colorless oil.
IR: 2940, 2862, 1728, 1375, 1;)57, 992, 840 cm~1~
For ~ilylether cleavage, 0.93 g of the above-produced acetate in 36 ~l of tetrahydrofuran is stirred with 1.1 g of tetrabutyla~monium fluoride for 1 hour at 0 and for 3 hours at 24C under argon. Then, it is diluted with diethyl ether, washed three times with water, dried on anhydrous magnesium sul~ate and concentrated by evaporation in a vacuum. The residue is chromatographed on silica gel~ With hexane/ethyl acetate mixtures, 0.65 g of (+/~ 5RS)-5-acetoxy-5-ttrans-(2RS)-2- -~(lE,3~)-(5RS)-5-acetoxy-1,3-tridecadienyl)-~lRS)-cyclobutyl3-pentan-l-ol is obtained as colorless oil.
IR: 3620, 3460, 2730, 2860, 1725, 1608, 1375, 1250, 992, 950 c~1.
For oxidation of the l-hydroxy group, 3.8 g of Collins reagent is added to 0.64 g of the above-produced alcohol (diastereomer B) in 70 ml of dichloromethane at 0C and stirred ~or 20 minutes at 0C. Then, it is diluted with a mixture of hexane/diethyl ether (1+1), Celite is added, filtered, washed with hexane/diethy:L ether (1~1) and concentrated by evaporation in a vacuum. The thus obtained l-aldehyde is immediately used without further purification.

~6 ~2~92 1.3 ml of Jones reagent is instilled in a solution of 0.6 g of ths above-produced aldehyde in 16 ml of acetone with stirring at -~5C and stirred for 15 minutes at -25C under argon. Then, 3 ml of 2-propanol is added, stirrecl ~or 5 minutes, diluted with 100 ml of diethyl ether, shaXen twice with semiconcentrated sodium chloride solution, dried on anhydrous sodium sulfate and , concentrated by evaporation in a vacuum. The residue is i chromatographed on silica gel. With hexa~e/ethyl acetate ~6+4~, 0O52 g of the title compound is obtained as colorless oil.
i IR: 3520, 2g30, 2860, 1725, 1658, 1360, 1250, 990, 946 cm~l.
., .
9a) 5-[trans-1-(tert.-Butyl-dimethylsilyloxymethyl~-cyclobut-2-yl]-(2E,4E)-pentadienoic acid ethyl ester A solution of 20 g of trans 1,2-cyclobutanedicarboxylic acid I dichloride in 40 ml of tetrahydrofuran is carefully instilled at ¦ -15C in a solution of 8.4 g o~ sodium borohydride in 280 ml of ethyl alcohol. After completion of the gas generation it is stirred for 30 minutes at -15~C and then 150 ml of water is slowly instilled. It is stirred for 30 minutes at 22C and then diluted with 1.5 liter of diethyl ether. It is shaken twice with water, twice with semiconcentrated sodium chloride solution, I dried on anhydrous sodium sulfate and concentrated by evaporation ¦ in a vacuum. The residue is purified by chromatography on silica gel. With ethyl acetate, 9.5 g of trans-1,2-dihydroxymethyl-¦ cyclopentane is o~tained as colorless liquid `~ IR: 3610, 3400, 2960, 1062 cm1 - :

, 47 2~3.~
,,, ~

22.7 g of imidazole and 25.1 g of tert.-butyldimethylsilyl chloride are added to a solution of 1903 g of trans-1,2-dihydroxymethyl-oyclopentane in 200 ml of dimethyl~ormamide at 0C and stirred for 22 hours at 24C. It is diluted with 1.5 1 of diethyl ether, shaken twice with 80 ml of 10% aqueous sul~uric acid each, washed neutral with water, dried on anhydrous magnesium sulfat~ and concentrated by evaporation in a vacuum.
The residue is chromatographed on silica gel. With hexane/ethyl acetate (8+2), 17 g of trans-1-(tert.-butyldimethylsilyloxymethyl)-2-hydroxymethyl-cyclopantane is obtained as colorless liquid.
IR: 3420, 2960, 2860, 1260, 840 cm~l.
70 g of Collins reagent is added to a solution of 14.9 g of the above-described monosilylether in 750 ml of dichloromethane and stirred ~or 30 minutes at 0C. Then, it is diluted with a mixture of hexane/diethyl ether (3+2), Celite is added, filtered and concentrated by evaporation in a vacuum. 13.8 g of the aldehyde is obtained, which is used without further purification.
IR: 2958, 2860, 2720, 1719, 840 ~m~1.
For Wittig-Horner olefination, 8 g of phosphonocrotonic acid triethyl ester and 4.9 g of diaza~icycloundecene ~DBU) are added at 24C to a stirred suspension of 1.37 g of lithium chloride in 250 ml of acetonitrile and stirred for 10 minutes. Then, a solution of 6.5 g of the above-described aldehyde in 50 ml o~
acetonitrile is instilled, stirred for 3.5 hours at 24C and then diluted with diethyl ether. It is shaken in successian with water, 10% aqueous citric acid solution and water, dried on 1 4~ 2122~2 ~ anhydrous magnesium sulfate and concentrated by evaporation in a .I vacuum. The residue is chromatographed with hexane~ethyl acetate on silica gel. In this way, 5.9 g of the title compound is obtained as colorless oil.
, IR: 2958, 2860, 1702, 1639, 1620, 1470, 125S, 1003, 'J' 8~0 cm~l.

9b) 5-~trans-1-(tert.-Butyl-dimethylsilylox~m~th~ cyclobut-2-yl]-(2E,4E)-pentadien-l-ol 33.5 ml of a 1.2 molar solution of diisobutylaluminum hydride in toluene is instilled in a solution of 5.2 g o~ the ester, produced according to example ~a, in 150 ml of toluene at -70C under argon and stirred ~or 30 minutes at -70C. Then, 16 ml of 2 propanol and, after 5 minutes, 16 ml of water are instilled, stirred for 2.5 hours at 23C, filtered, washed with . dichloromethane and concentrated by evaporation in a vacuum. The I residue is purified by chromatography on silica gel. With I hexane/diethyl ether (7+3), 4.85 g of the alcohol is obtained as colorless oil.
IR: 3610, 3450, 990, 840 cm~1.
. For aldehyde production, a solution of 4.8 g of the above-produced alcohol in 100 ml of toluene is mixed with 15 g of : manganese dioxide and stirred ~or 3 hours at 24C. Then, it is filtered, concentrated by evaporation and chromatographed on silica gel. With hexane/ethyl acetate (8+2), 4.5 g of the title . compound is obtained as colorless oil.
IR: 2960, 2860, 2740, 1680, 1633, 990, 940, 840 cm~
. ,~ ' .' `:
.

49 ~ 32 9c) (5RS)-5-Acetoxy-l-ttrans-l-(tert.-butyl-dimethylsilyloxymethyl)-cyclobut-2-ylJ-l-(lE,3E) tridecadiene A solution of 8.9 g of octyl bromide in 10 ml of diethyl ether is instilled in 1.12 g of magnesium in 4ml of diethyl ether with heating and stirred for 30 minutes at ~5C.
~ solution of 4.~ g of aldehyda, produced according to example 9b, in 50 ml of diethyl eth~!r is instill~d in 8.33 ml (=mmol) of this Grignard solution at 20~C under argon and stixred for 45 minutes at -20C. It i~ mixed with saturated ammonium chloride solution, extracted three times with diethyl ether, the organic phase is shaken with semiconcentrated sodium chloride solution, dried on anhydrous sodium sul~ate and concentrated by evaporation in a vacuum. The residue is chromatographed on silica gel. With hexane/ethyl acetate (6~4), 6.1 g of alcohol (diastereomer mixture) is obtained as colorless oil.
For acetylation, 10 ml of acetic anhydride is added to a solution of 6.05 g of the above-produced alcohol in 20 ml of pyridine and stirred for 23 hours at room temperature. Then, it is concentrated by evaporation in a vacuum while adding toluene and the residue is chromatographed on silica gel. With hexane/ethyl acetate (9+1), 6.4 g of the title compound is obtained as colorless oil.
IR: 2938, 2860, 1725, 1658, 1255, 991, 945, 840 cm~1.

' 50 ~22~2 .

9d) trans-(lRS)-l-Formyl-(2RS)-2-~(lE,3E)-(5RS)-5-acetoxy-1,3-tridecadienyl]-cyclobutane 9.2 g of tetrabutylammonium fluoride is added to a solution of 6.3 g of the acetate, produced according to example 9c, in 160 ml of tetrahydrofuran at 0C, stirred for 15 minutes at O~C and for 3 hours at 24Co Then, it is di]Luted with 1 1 of diethyl ether and washed three times with semiconcentrated aqueous sodium chloride solution. It is dried with anhydrous sodium sulfate, concentrated by evaporation in a vacuum and the residue is chromatographed on silica gel. With hexane/ethyl acetate (7+3), 4.4 g of the alcohol is eluted as colorless oil.
IR: 3625, 3450, 2932, 2862, 1728, 1680, 1250, 991 cm~1.
~ 8 g of Collins reagent is added to a solution of 4.3 g of the above-produced alcohol in 130 ml of dichloromethane at 0C
and stirred for 20 minutes at 0C. Then, it is diluted with a mixture of hexane/diethyl ether ~1~1), Celite is added, ~iltered and concentrated by evaporation in a vacuum. The thus obtained aldehyde was used without further purification.
IR: 2930, 2~60, 2721, 1721, 1250, 990 cm~1.

Bxample 10 3-(5RS)-5 ~ydro~y-5 [tran~-(2R~)-2-l~lE,3E)-~5RS3-5-hydro~y-1,3-tridecadie~yl)~lRS)-~yclobutyl]-pe~tanoic acid Diastereomer B
Analogously to example 2, 134 mg of the title compound is obtained as colorless oil from 180 mg of the diacetate, produced according to example 9.

; ~ . ., . . . ~. ~ ,,.. .... . ... -51 ,, ~122992 ilm~: 3450, ~92~, ~85~, 1714, 16~0, 1~50, 989, 930 cm-1.
' E:~ampl~ 11 ~ (5R~-5-~cato~-5-ttrans-~2R~)-2~ ,3~ 5R~ 5-hy~ro~-1,3-tridecadie~yl)-~lR~)-cyolobutyl~-penta~oio Di~stereomer B
; Analogously to example 3, 46 mg of the title compound is obtained a~ colorless oil from 200 mg of the diacetate, produced according to example 9.
IR (film~: 3450, 2930, 2860, 1730, 1710, 1660, 1275, 9gO cm~1.
~, .
~xample 12 SR~) 5-Acetox~-5-ttra~s-(2Rg)-2-t(lE~3E)-~5R~)-5-aceto~y-1,3-triaeo~dienyl)-(lR8)-cyclobutyl]-pe~t~noic acid Diasteroomer A
3.8 g of Collins reagent is added to a solution of 0.64 g of the l-alcohol from the nonpolar alcohol (diastereomer A), . produced according to example 9 by acetylation and silylether : cleavage in 70 ml of dichloromethane at 0C and stirred for Z0 minutes at 0C. Then, it is diluted with a mixture of hexane/diethyl ether (1+1), Celite is added, filtered, washed ¦ with hexane/diethyl ether (1+1~ and concentrated by evaporation . in a vacuum. The thus obtained 1-aldehyde is immediately used without further purification.

'.' ^ 5Z
, 2122tq,~2 1.3 ml of Jones reagent is instilled in a solu~ion of 0.6 g of the above-produced aldehyde in 16 ml o~ acPtone with stirring : at ~25C and stirred for 12 minutes at -25~C under argon. Then, 3 ml of 2-propanol is added, stirred for 5 minutes, diluted with diethyl ether, shaken with semiconcentrated aqueous sodium chloride solution, dried on anhydrolls sodium sulfate and concentrated by evaporation in a vac~uum. ~he residue is chromatographed on silica gel. With hexane/ethyl acetate (6~4), 0.52 g of the title compound is obtained as colorless oil.
. IR: 3520, 2930, 2860, 1724, 1658, 1373, 1250, 989, '' 946 cm7.
. :
Example 13 ~ (5R8)-5-Hydroxy-5-~trans-(2R8)-2-(~lE,3B) (5R~)-5-hydroxy-¦ ~,3-tri~ecadienyl)-~lR~)-cyclobutyl~penta~oic ~cid ¦ Diastereomer A
Analogously to example 2, 153 mg of the title compound is obtained as colorless oil from 200 mg of the diacetate, produced according to example 12.
IR: 3600, 3420, 2930, 2859, 1730, 1660, 1250, 990 cm~7.

53 ~22~92 E~ample 14 (5R~)-5-Aceto~-5- r tra~ R~)-2~ E,3E)-~5R~3 5 hydlro~y-1~3-triaeoa~iehy~ lPs~)-oyclobutyl]-penta~ aoi~
Dia~3tereomer A
Analogously tc example 3, 174 mg of the title compound is obtained as colorless oil from 200 mg of the diacetate, produc~d according to example 12.
IR ~ilm): 3610, 3450, 2930, 2860, 1724, 1660, 1250, 990 cm~t. . .

E~ample 15 t~ 15R~) 5-~ydro~y-5-t~is-~2R8)-2~ E) - ~5R~ ~-5-hy~roxy-l,3~tridecadienyl)-~lR&)-cyalobutyl3-pentanoic acid methyl ester Dia~tereomer polar ~51 An ethereal diazomethane solution is instilled in a solution of lO0 mg of the acid, produced according to example 2, in lO ml of dichloromethane at 0C until permanent yellow coloring and stirred for 15 minutes at 0C. Then, it is concentrated by evaporation in a vacuum and the residue is chromatographed on silica gel. With hexane/ethyl acetate (2+8~, 69 mg of the title compound is obtained as colorless oil.
IR (film~: 3600, 2925, 2as5, 1738, 1658, 990 cml.
-. , 5~ 2~ 3 g2 ,--E~ample 16~ 5R8)-5-~ydro~y 5-tais (2RS)-2~ ~lE~3E)-~5RS~ 5-hy~roxy 1,3-trideoadienyl)~ cyalobutyll-pe~ta~oi~ acid methyl e3t~r Dia~tereomer ~onpolar S5 Analogously to examp~e 15, 95 mg of the title compound is obtained as oil from 110 mg of the acid, produced according to example 6.
IR (film): 3610, 2925, 2855, :L738, 1660, 990 cm~1.

E~pl~ ~Y
~ 5RB)-5-A¢etosy-5-[cis ~2~ 2 ((1~,3~)~;(5R~) 5 hydroxy-1,3-tridecadie~yl)-~lR8)-¢yclobu~yl]-pentanoic a¢i~ methyl e8ter Dia~tereomer polar S5) Analogously to example 15, 71 mg of the title compound is obtained as colorless oil from 70 mg of the acid, produced according to example 3.
IR (film): 3400, 2924, 2858, 1739, 1658, 1240, 990 cm10 Example 18 (~/-)-~5R~3-5-~ydro~y-5 tci~-(2R~)-2 t~1~,3~1-(5RS)-5-hy~roxy-1~3-tri~e$aaie~yl~-~lRS)-cyclobutyl~-penta~oic acid-tris-thydro~ethyl)-aminometha~e salt DiaQtereomer polar (5) A solution of 15 mg of tris-(hydroxymethyl)-aminomethane in 0.03 ml of water is added to a solution of 40 mg of the carboxylic acid, produced according to example 2, in 6 ml of acetonitrile at 70C. It is allowed to cool with stirring, is ~12 2 ~ 92 decanted after 16 hours from the solvent and the residue is dried in a vacuum. 1~ mg of the title compound is isolated as waxy mass.

~xampl~ 19 ~ )o(5R~-5 ~ydroxy-5-[oi~-~2R~-2~1B~3B) ~5R~)-5-hydroxy-1~3-tri~eoa~ie~yl) ~lR8~-ayalobutyl3~pe~ta~oic aGid-~,5-la¢to~e I)ia8~ereomer polar (5~
0.9 g of anhydrous magnesium sul~ate i~ added to a solution o~ 53 mg of the carboxylic acid, produced according to example 6, in 9 ml of toluene at 24C over a period of 24 hours in portions and stirred for another 24 hours at 24C~ Then, it is filtered and the evaporation residue is chromatographed on silica gel.
With toluene~ethyl acetate (7+3), 28 mg of the 1,5-lactone is eluted as colorless oil.
IR: 3600, 2930, 2860, 1729, 1250, 990 cm-1.

E~mpl~ 20 ~ 5RSl-5-Acetoxy-5-~cis-(2RS)-2-((lE,3E)-(5R or 5S~-5-acetoxy-1 3-tridecadienyl)-(lRS)-cycloheptyll-pentanoic acid (diastereomer A) A solution of 1.09 g of 4-chlor-1-(tert.-butyl-dimethylsilyloxy)-butane in 1 ml of tetrahydrofuran is instilled in 238 mg of magnesium at 24C under argon, a crystal of iodine is added, heated for 10 minutes to 70C, stirred for 30 minutes at 24C and diluted with 3 ml of tetrahydrofuran.

--` 56 ~:~22~92 The above-produced Grignard sol~tion is instilled in a solution of 467 mg of cis-(lRS)~ ormyl(2RS)-2 [(~E,3E)-(5R or 5S)-,-acetoxy-1,3~tridecadienyl-cycloheptane (diastereomer A) from example le) in 2.6 ml of tetrahydrofuran at -70C under argon, it is allowed to warm to -30C and is stirred for l hour at this temperature. The reaction mixture is added to lO0 ml of saturated ammoniumi chloride solution and extracted three times eiach with 100 ml ethyl acetate. The combined organic phases are washed once with semico~centrated aqueous sodium chloride solution, dried on anhydrous sodium sulfate and, a~ter ~iltration, concentrated by evaporation in a vacuum. l~he thus ~btained residue is purified by chromatography on silica gel.
With hexane/methyl-tert.-butyl ether (92~8), 351 mg of 5-(tert.-butyldimethylsilyloxy)-l-cis-~2-~(lE,3E)-(5RS)-5-acetoxy-1,3-tridecadienyl]-cycloheptyl}-pentan-l-ol is obtained as colorless oil.
IR (CHCl3). 3690, 3610, 3440 (broad), 3005t 2932, 2860, 1727, 1465, 1375, 1247, 1098, 995, 840 cm~1.
For acetylation, 0.5 ml of acetic anhydride is added to a solution of 345 g of the above-described alcohol in 1 ml o~
pyridine and stirred ~or 6 hours at 24C. Then, it is diluted with water and conc2ntrated by evaporation in a vacuum while adding toluene. The thus obtained residue is purified by chromatography on silica gel. With hexane/0-lO~ethyl acetate, 347 mg of the acetate is obtained as colvrless oil.
IR (CHCl3): 3002, 2930, 2860, 1725, 1464, 1374, 1243, 1100, 993, 338 cm~~.

57 2 ~22~2 ., ~

For silylether cleavage, 344 m~ of the above-produced acetate in 2.3 ml of tetrahydrofuran is stirred with 366 mg of tetrabutylammonium ~luoride trihydrate for 3 hours at 24C under argon. Then, it is diluted with 100 ml of diethylether, washed three times each with 20 ml of water, once with saturated aqueous sodium chloride solution9 dried on anhydrous sodium sulfate and~
after filtration, concentrated by evaporation in a vacuum. 314 mg of ~+/-)-(5RS)-5-acetoxy-5-tcis-(2RS)-2-((lE,3E3-(5RS)-5-acetoxy-1,3-tridecadienyl)-(lRS~-cycloheptyl~ pentan-l-ol is obtain~d as oil. The latter is dissolved without furth~r purification in 15.5 ml of dichloromethane, mixed under argon at 0C with 2.63 g of Collins reagent (bis-pyridin-chromium(VI)-oxide complex, Tetrahedron Letters 1968, 3363) and stirred for 1 hour at 0C. Then it is diluted with diethyl ether, mixed with Celite, filtered of~ over Celite and rewashed well with diethyl ether. The l-aldehyde obtained after concentration by ~vaporation is immediately dissolved without further purification in 13.8 ml of acetone, mixed at -30C under argon with 0.35 ml of Jones reagent (chromium(VI)oxide in H2S04) (J. Chem. Soc. 1953, 2555) and stirred for 20 minutes at this temperature. Then 0.15 ml of 2-propanol is added, stirred for 10 minutes, diluted with 70 ml of ethyl acetate, shaken four times with 20 ml of semiconcentrated aqueous sodium chloride solution each, dried on anhydrous sodium sulfate and, after filtration, concentrated by evaporation in a vacuum. The thus obtained residue is purified by chromatography on silica gel. With hexane/0-50% ethyl `:. 2122~'~S~
~ 58 . . . ~

acetate, 117 mg of the title compound is obtained as colorless ~il .
IR (~ilm): 3450, 3190 (broad), 3022, 2925, 2855; 1737, 1710, 56, 1370, 1240, 990 cm~1.
The initial material for the above title compound i5 produced as follows:
20a) cis-1,2-b~ hydroxymeth~l)-cvcl~h~ptane 13.0 g o~ ci~-1,2-cycloheptanedicarboxylic acid anhydride (J. Sicher et al., Collection Czechoslov. Chem. Commun. 26~ 262 (1961) is dissolved in 13.8 ml of toluene and 18.~ ml o~
methanol. A~ter addition of 128 mg of p-tolu~ne sulfonic acid, it is refluxed for 20 hours. After concentration by evaporation, the residue i8 taken up in 18.8 ml of methanol and refluxed again ~or 20 hours. A~ter concentration by evaporation, the thus obtained residue is dissolved in 950 ml of toluene and mixed with 350 ml of a 1.2 ~olar solution of diisobutylaluminum hydride at -78C under argon. It is allowed to heat for 2 hours to 0C, then 50 ml of isopropanol, drop by drop followed by 175 ml of water, is carefully added at -70C and then stirred ~or 2 hours at 24C. It is filtered off from the precipitate, washed well with ethyl acetate and concentrated by evaporation in a vacuum.
The thus obtained residue is purified by chromatography on silica gel. With hexane/0-70~ ethyl acetate, 6.67 g of the title compound is obtained as colorless oil.
IR~CHCl3): 3625, 3370 (broad), 3005, 2930, 2862, 1460, 1380, 1075, 1040 cm~1.

, , 59 2~22992 20b) 5-rcis~trans~ tert.~but~l-dimethylsilyloxymethyl)-cyclohept-2-yl~-(2E,~ 2,4-pentadienoic acid ethyl ester A s~lution of 14.9 g of the above-produced diol in 10 ml o~
tetrahydrofuran is carefully instilled in a suspension of 4.1 g of sodium hydride ~55% in mineral oil) in 180 ml of tetrahydrofuran at 0C under argon. It is stirred for 45 minutes at 24C and then 14.1 g o~ tert.-butyl-dimethylsilyl chloride is added at 0C. It is stirred for one hour at 24C and diluted with 1000 ml of ether. The organic phase is washed with 200 ml of 10~ aqueous potassium carbonate solution and ~our times with 100 ml of saturated aqueous sodium chloride solution each. After drying on anhydrous magnesium sulfate and filtration it is concentrated by evaporation in a vacuum. The thus obtained residue is purified by chromatography on silica gel. With hexane/0-30% ethyl acetate, 22.7 g o~ cis l-tert.-butyl-dimethylsilyloxymethyl)-2-hydroxymethyl-cycloheptane is obtained as colorless oil.
IR(CHCl3): 3420 (broad), 3008, 293~, 2862, 1470, 1262, 1060, 843 cm~l.

, 19.5 g of dimethylsulfoxide dissolved in 42.6 ml of , dichloromathane is carefully instilled in 14.8 g of oxalylchloride dissolved in 104 ml of dichloromethane at 60C
under argon and stirred for 10 minutes at this temperature~ Then a solution of 22.7 g of the above-produced alcohol in 42.6 ml of , ~ichloromethane is instilled and stirred for 1 hour at -60C.
Then 26.3 g of triethylamine is added and, after 1 hour of I

I

~ . . 60 2122-9~J2 stirring at -60c, the reaction mixture is added to 300 ml of ice water. After phase separation the aqueous phase is extracted three times with 300 ml of dichloromethane each. The combined organic phases are washed neutral with lO0 ml of 10% aqueous citric acid and then with semiconcentrated aqueous s~dium chloride solution. A~ter drying on magnesium sulfate and filtration it is concentrated by evaporation in a vacuum. 22.9 g of the aldehyde is obtained that is used without further puri~ication.
IR(CHCl3): 3005~ 2935, 2862, 2740, 1720, 1475, 1258, 1100, 840 cm~1.

, 36.6 g of 4-phosphonocrotonic acid triethyl ester followed by 12.9 g of DBU (diazabicycloundecane) is instilled in a ~uspension o* 4.31 g of lithium chloride in ~30 ml of acetonitrile at 24C under argon and stirred for 10 minutes at this temperature. Then a solution of 22.9 g of the above-produced aldehyde in 69 ml of acetonitrile is slowly instilled and stirred for 5 hours at 24C. Then it is diluted with 1.5 l of diethyl ether, the phases are separated, the organic phase is washed in succession with 100 ml o~ water and 10% aqueous citric acid. After washing neutral with semiconcentrated aqueous sodium chloride solution and drying on anhydrous magnesium sulfate, it is concentrated by evaporation after filtration. The thus obtained residue is purified by chromatography on silica gel.
With hexane/0-10% diethyl ether, 14.53 g of the title compound is obtained as colorless oil.

:

' - ' 61 2-12~ 2 IR(CHCl~: 30430, 2940, 2870, 1710, 1~45, 1622, 1470, 1378, 1310, 1255, 1100, 1008, 843 cm~1.

20c) -rcis,~trans 1-(tert.-butyl-dimethylsilylo~methyl~-cyclohe~t-2-yll-L~ EL~-pentadien-l-al 102 ml of a 1.2 molar solution of diisobutylaluminum hy~ride in toluena is instilled in a soluti~Dn of 14.5 g of the ab~ve-produced ester in 270 ml o~ toluene at -70C under argon and allowed to heat to 0C within 2 hours. 5 ml of 2-propanol followed by 51 ml of water is carefully added at -70C and then stirred for 2 hours at 24C. It is filtered off from the precipitate, washed well with ethyl acetate and concentrated by evaporation in a vacuum. The thus obtained residue is purified by chromatography on silica gel. With hexane/0-lO~ ethyl acetate, 9022 g of 5-[cis/trans-1-(tert.-butyl-dimethylsilyloxymethyl)~cyclohept-2-yl~-(2E,4E)-2,4-pentadien-1-ol is obtained as colorless oil.
IRtCHCl3): 3420 (broad), 2940, 2865, 1630, 1465, 1100, 995, 840 cm~1.

s ;l A solution of 9.21 g of the above-produced alcohol in 107 ml of dichloromethane is mixed with 19.7 g of manganese dioxide and stirred for 18 hours at 2~C under argon. Then it is filtered and concentrated by evaporation in a vacuum. 8.57 g of the title i compound is obtained as colorless oil, which is used without further purification.

!

~ 62 2122~2 IR(CHCl3~: 3005, 2935, 2863, 2748, 1680, 1637, 1603, 1467, 12~0, 1100, 990, 840 cm~1.

20d~ (5R or 5S~-5-Acetoxy-l-rcis-l-hydrox~ethyl-cyclohept-2~yl~-(lE,3E~-trideca-1 3-diene ldiastereomer AL
A solution of 6~15 g of octyl bromide in 50 ml of j tetrahydro~uran is instilled in 774 mg of magnesium in 50 ml o~
- tetrahydrofuran with heating and stirred for 30 minutes at 24C.
This Grignard solution is instilled in a solution of B.56 g of ~he aldehyde produced in lc) in 50 ml of tetrahydrofuran at -30C
under argon and stirred for 30 minutes at this temperature.
After heating to -10C the reaction mixture is added to 500 ml of saturated aqueous ammonium chlorid~ solution. It is extracted Z three times with 300 ml of ethyl acetate each and the combined ¦ organic phases are then washed with saturated aqueous sodium chloride ~olution. After drying on anhydrous magnesium sulfate and filtration, it is concentrated by evaporation in a vacuum.
The ~h~s o~tained residue is purified by chromatography on silica ¦ gel. With hexane/0-20~ diethyl ether, 7.40 g of (5RS)-5-hydroxy-l-[cis/trans-1-(tert.-butyl-dimethylsilyloxymethyl)-cyclohept-2-~j yl3-(lE,3E)-trideca-1,3-diene is obtained as colorless oil.
IR~CHCl3): 3700, 3520 (broad), 3005, 2932, 2860, 1465, 1095, 992, 840 cm~1.

A solution of 7.39 g of the above-produced alcohol in 26.6 ml of pyridine is mixed with 13.3 ml of acetic anhydride at 0C
under argon and stirred at this temperature for 16 hours. Then .

63 ~, L22992 :, .
it is mixed with 50 ml ~f waker and concentrated by evaporation in a vacuum with addition of toluene. The thus obtained residue is purified by chromatography on silica gel. With hexane~0-5%
diethyl ether, 8.1 g of (5RS) 5-acetoxy-1 ~cis/trans-l-(tert.-7 butyl-dimethylsilyloxymethyl) -cyclo]hept-~-yl]-(lE,3E)-trideca-1,3 rdiene i5 obtained as colorless oil.
IR(CHCl3~: 3005, 2930, 2860, 1725, 1465, 1375, 1253, 1095, 992, 840 c~

-7 12.1 g of tetrabutylammonium fluorida trihydrate i~; added in ~7 a solution of 8.1 of the above-produced acetate in 77.5 ml of tetrahydrofuran at 24C under argon and stirred at this temperature for three hours. Then it is diluted with 500 ml of diethyl ether, washed three times each with 100 ml of water and once with saturated aqueous sodium chloride solution. After drying on anhydrous magnesium sulfate and filtration, it is concentrated by evaporation in a vacuum. The thus obtained ~¦ residue is separated by multiple chromatography on silica gel.
With hexane/ethyl ac:etate (85~15), ~our fractions (classified according to increasing polarity) are obtained.
1st fraction: 1.63 g of (5R or 5S)-5-acetoxy-1-[~rans-1-hydroxymethyl-- yclohept-2-yl]-(lE,3E)-trideca-1,3-diene (diastereomer A) IR(CHCl3): 3625, 3460 (broad), 3005, 2935, 2862, 1730, 1468, ;~ 1378, 1253, 1020, 995 cm~1.
:2nd fraction: 517 mg of the title compound I

64 ~1 22~2 ., ,~ .
IR(CHCl3): 3620, 3450 (broad~, 3005, 2930, 2860, 1725, 1458, 1375, 1252, 1017, 9g2 cm~1.
3rd fraction: 1.36 g of ~5S or 5R)-5-acetoxy-1-[trans-1-hydroxymethyl~cyclohept-2-yl]-(lE,3E)-trideca-1,3~diene (dia~tereomer B) IR(CHCl3): 3620, 3450 ~broad~, 3005, 2930, 2860, 1728, 1465, 1375, 1248, 1017, 990 cm~1.
4th fraction~ 767 mg of ~5S or 5R)-5-acetoxy-1-~cis-1-hydroxymethyl-cyclohept-2-yl]-~lE,3E)-trideca-1,3-diene (diastereomer B of the title compound) IR(CHCl3): 3620, 3450 ~broad), 3005, 2930, 2860, 1728, 1460, 1375, 1250, 1017, 992 cm~1.

20e) cis-(lR~-Formyl-(2RS)-2-((lE,3E)-(5R or 5~L_5-acetoxy~l,3-trid~cadienyl)-cycloheptane (diastereomer Al 2.21 g of Collins reagent is added to a solution oP 501 mg of the alcohol produced according to example ld) in 37 ml of dichloromethane at 0C under argon and stirred for 80 minutes at 0C. Then it is diluted with diethyl ether and mixed with Celite, filtered off on Celite and washed well with diethyl ether. After concentration by evaporation in a vacuum, the thus o~tained title compound is used without further purification.
IR(CHCl3): 3005, 2935, 2860, 2740, 1725, 1460, 1375, 1250, 9 9 0 Clll 1 .

~ 65 ~ 2~2~992 Example 21 (+J_)_(5RS~ 5-Acetoxy-5-rcis-(2RS)-2-~[[lE~3E)-(5R or 5S)-5-hydroxy-iL~ tridecadieny~ RsL-cycloheptyll~pentanoic acid ~diastereomer A) 0.9 ml of a 0.5N aqueous sodium hydroxide solution is added to a solution of 4~.3 mg of the diacetate, produced in example 1), in 0.9 ml of methanol and stirred for 2 hours at 2~C. Then it is mixed with 20 ml of water and adj~sted to pH 5 wlth a lN
aqueous hydrochloric acid. Then it is ~xtracted thres times each with 30 ml of ethyl acetate, the combined organic phase,s are waghed with 10 ml saturated aqueous sodium chloride solution, dried on sodium sulfate and after filtration concentrated by evaporation in a vacuum. The thus obtained residue is purified by chromatography on silica gel. With hexane/0-90% ethyl acetat~, 34 r 3 mg of the title compound is obtained as colorless oil.
IR(film): 3~30 ~broad), 3020, 2925, 2855, 1735, 1710, 1456, 1371, 1242, 990 cm~1.

E~ample 22 (+/-)-(5RS)-5-Hydroxy-5-Ccis-(2RS)-2-fflE.3E)-(5R or 5S)-5-hydroxy-1 3-tridecadienyl- ! lRS)-cycloheptyl~-pentanoic acid (diastereomer A) and (~ 5RS)-5-hydroxy-5-rcis-f2RS)-2-((lE.3E)-f5R or 5S)-5-hydroxy-1,3-tridecadienyl-(lRS)-cycloheptyll-p~ tanoic acid-1,5-lactone (diastereomer A) 4.3 ml of a lN aqueous sodium hydroxide solution is added to a solution of 68.5 mg of the diacetate, produced in example 1), '~' 66 2'122r~'~92 in 2.85 ml of methanol and stirred ~or 18 hours at 24c. Then it is mixed with 30 ml of water, washed once with ethyl acetate and th~ pH of the aqueous phase is adjusted to 5 with a lN aqueous hydrochloric acidO Then it is extracted three times each with 30 ml of ethyl acetate, the co~bined organic phases are washed with 20 ml of semiconcentrated sodium chloride solution, dried on anhydrous sodium sulfate and after filtration concentrated by evaporation in a vacuum. The thus obtained residue is purified by chromatography on silica gel. With hexane/0-100~ ethyl acetate, as nonpolar component ~9.7 mg of (~ (5RS)-5-hydroxy-

5-[cis-(2RS)-2-((lE,3E)-(5R or 5S)-5-hydroxy-1,3-tridecadienyl-(lRS)-cycloheptyl]-pentanoic acid-1,5-lactone (diastereomer A) and as more polar component 4.8 mg of (+/-)-(5RS)-5-hydroxy-5-tCiS~(2RS)-2~ E,3E)-(5R or 5S)-5-hydroxy-1,3-tridecadienyl-(lRS)-cycloheptyl]-pentanoic acid (diastereomer A) are obtained as colorless oils.
IR (Film; lactone): 3440 (broad), 3020, 2927, 2855, 1733, 1460, 1377, 1242, 991 cm~l.
IR ~CHCl3; acid): 3440 (broad), 3005, 2925, 2860, 1725, 1462, 1380, 1240, 990 cm~

Example 23 ~ +~ 5R or 5S)-5-Acetoxy-5-Lcis-(_RS)-2-~(lE 3E)-(5S or 5R)-5-acetoxy-1,3-tridecadienyl-~lRS)-cycloheptyll-pentanoic acid tdiastareomer B, nonpolar 5 A solution of 1.39 g of ~-chloro-l-(tert.butyl-dimethylsilyloxy)-butane in 1.2 ml of tetrahydrofuran is ~ 67 ~ 223'~2 ;~ .
instilled in 303 mg of magnesium at 24C under argon, a crystal of iodine is added, heated for lO minutes to 70C, stirred for 30 minutes at 24C and diluted with 3.9 ml of tetrahydrofuran.
The above-produced Grignard solution is in~tilled in a solution of 595 mg of cis-(1RS)~ ormyl-(2RS)-2~r(1E,3E)-(5S or 5R~-5-acetoxy-1,3-tridecadienyl-cycloheptane (diastereomer B) from example 4a) in 3.3 ml of tetrahydrofuran at -70C under argon and allowed to heat to -30C and stirred ~or 1 hour at this temperature. The reaction mixture is added to 100 ml of saturated ammoniumchloride solution and extracted three times with ethyl acQtate. The combined organic phases are washed once with semiconcentrated aqueous sodium chloride solution, dried on anhydrous sodium sulfate and after filtration concentrated by evaporation in a vacuum. The thus obtained residue is purified by multiple chromatography on silica gel. With hexane/ethyl acetate (90~10), 131.4 mg of the nonpolar diastereomer alcohol ~nonpolar 5) and 404.7 mg of the more polar diastereomer alcohol (polar 5) are obtained as colorless oil.
IR (film; nonpolar alcohol): 3650, 3460 (broad), 3022, 2925, 2865, 1734, 1462, 1370, 1248, 1100, 990, 835 cm~1.
IR (film; polar alcohol~: 3650, 3460 (broad), 3025, 2930, 2857, 1735, 1237, 1460, 1372, 1100, 990, 836 cm~

For acetylation 0.2 ml of acetic anhydride is added to a solution of 129 mg of the above-described nonpolar alcohol in 0.4 ml of pyridine and stirred for 6 hours at 24C. Then it is concentrated by evaporation in a vacuum with addition of toluene.

6~ 2~2~92 ,~
'i The thus obtained residue is purified by chromatography on silica gel~ With hexane/o-10% ethyl acetate~ 81.2 mg of the acetate is obtained as colorless oil.
IR(CHCl3): 3005, 2930, 2860, 1725, 1465, 1375, 1255; 992, 838 cm-1 For silylether clea~age 77.2 ~Ig of the akove-produced acetate in 0.5 ml of tetrahydro~ura~ is stirred with 91.3 mg of tetrabutylammonium fluoride trihydrate at 24C under argon for 3 hours. Th~n it is diluted with 70 ml of diethyl ether, washed three times with 20 ml of water each, once with saturated a~ueous sodium chloride solution, dried on anhydrous ~odium sulfate and~
after filtration, concerltrated by evaporation in a vacuum. Aftar filtration on silica gel with hexane/ethyl acetate, 47.1 mg of 1-alcohol is obtained as colorless oil. The alcohol is dissolved in 6 ml of ethyl acetate and stirred with addition of 440 mg of platinum(IV)oxide in an oxygen atmosphere for 4 hours. Then it is suctioned off`from the catalyst and concentrated by evapoxation in a vacuum. The thus obtained residue is purified by chromatography on silica gel. With hexane/0-50~ athyl acetate, 41.3 mg of the title compound is obtained as colorless oil.
IR(CHCl3): 3625, 3490 (broad), 3005, 2930, 2850, 1725, 1468, 1373, 1252, 992 cm~1.

The initial material for the above title compound is produced as follows:

~ '. 69 2 ~22~92 3 23a~ cis-(~RS~ ormyl-(2R5)-2- ~lEr3~)-(5S or ~R)-5-acetoxy-1,3-tridecadienyl)-cycloheptane (diastereomer B) Analogously to example le) 595 mg of the title compound is obtained ~rom 753 mg of ~5S or 5R)-5-acetoxy-1-rcis~l-hydroxymethyl-cyclohep~-2-yl]-(lE,3~ trideca-1,3-dien~
~diastereomer B, ~th ~raction from example ld))l that is used without further puriEication.
IR(CHCl3~: 3005, 2935, 2858, 2742, 1725, 1460, 1372, 1250 990 cm~10 ~ample 2~
(+~-)-(5S or 5R)-5-Acetoxy-5-~cis-(2RS)-2-((lE,3E)-~5S or 5R~-5-acetoxy~1,3-tridecadienyl-(lRS)-cycloheptyll-pentanoic acid (diastereomer B, polar 5) ~
For acetylation 0.6 ml of acetic anhydride is added to a solution of 400 mg of polar alcohol, obtained in example 23, in 1.2 ml pyridine and stirred for 6 hours at 24C. Then it is concentrated by evaporation in a vacuum with addition of toluene.
The thus obtained residue is purified by chromatography on silica gel. With hexane/0-10% ethyl acetate, 322.7 mg of acetate is obtained as colorless oil.
IR(CHCl3~: 3005, 2930, 2858, 1725, 1464, 1375, 1253, 992, 838 cm~1.

For silylether cleavage 318.7 mg of the above-produced acetate in 2.1 ml of tetrahydrofuran is stirred with 376.7 mg of tetrabutylammonium fluoride trihydrate at 24C under argon for 3 ~.~ . 70 2 '~ 9 ~ 2 ~J~
hours. Then it is diluted with 150 ml o~ diethyl ether, washed thrae times with 30 ml of water each, once with saturated aqueous sodium chloride solution, dried on anhydrous sodium sulfate and, after filtration, concentrated by evaporation in a vacuum. After . filtration on silica gel with hexane/ethyl acetate, 198 mg o~ 1-.:
. alcohol is obtained ~s colorless oil. The alcohol is dissolv2d in 26 ml of ethyl acetate and stirred with addition of 1.95 g of platinum(IV)oxide in an oxygen atmosphere for 4 hour~. Then it is suctioned off from the catalyst and concentrated by evaporation in a vacuum. The thus obtained residue is puriPied . by chromatography on silica gel. With hexane/0-50~ ethyl acetate, 200 mg o~ the title compound is obtained as colorless oil.
: IR~CHCl3): 3625, 3480 (broad), 3005, 2930, 2860, 1725, 14S5, ~ 1373, 1250, 990 cm-1.

: ~ample 25 : (+~ f5~ or 5S~-5-Acetoxy-5-[cis (2RS~-2-((lE.3E)-(5S or 5R)-5-hyd~oxv-1~3-tridecadienyl-(lRS)-cyclohe~tyll-pentanoic acid Sdiastereomer B, nonpolar 5~
Analogously to example 21, 18.7 mg of the titl~ compound is obtained as colorless oil from 41 mg of (+/-)-(5R or 5S)-5-acetoxy-5-tcis-(2RS)-2-((lE,3E)-(5S or 5R)-~-acetoxy-1,3-. tridecadienyl-(lRS)-cycloheptyl]-pentanoic acid (diastereomer B, ¦ nonpolar 5) from example 4).

IR (film): 3440 (~road), 3020, 2928, 2858, 1737, 1713, 1458, 1375, 1442, 990 cm~1.

~ 2~2~ 2 ~ ' 71 ~ ,~

E~ample 26 ~ (+~-3 ~5S or 5R~-5-Acetoxy~-Ccis-(2RS~-2-~(lE,3E)-(5S or `~ 5R)-5-hydroxy~1.3-tridecadi nyl-(lRS~-cy_loheptyl~-pentanoic acid . (diastereomer B, polar 5) ~ nalogously to example 21, 62~4 mg of the title compound is obtained as colorless oil from 80 mg of (+/~)-(5S or 5R)-5-acetoxy-5-[cis-(2RS)-2-((lE,3E) t5S or 5R) 5-acetoxy-1,3-tridecadienyl-(lR5)-cycloheptyl~-pentanoic acicl ~diastereomer B, polar 5~ ~rom example 5).
. IR (film): 3415, 3100 (broad), 3015, 2920, 2848, 1727, 1695, 1465, 1375, 1255, 990 cm~1.

B~ample 27 . (+/~2-(5S or 5~-5-Hydroxy-5-[cis-(2RS)-2-[(lE,3E)-(5S_or 5RL-5-hydroxy-1!3-tridecadienyl-(lRS)-cycloheptyl]-pentanoic acid (diastereomer B, polar 5L and (~ (5S or 5R1-5-hydroxy-5-rcis-~2~S)-2-((lE,3E~-(5S or 5R)-5-hydroxy-1,3-tridecadienyl-(lRS~-: cycloh~e~yl]-pentanoic acid-1,5-lactone (diastereomer B, ~olar 5) : Analogously to example 22, 42.6 mg of (~ (5S or SR)-5-hydro~y-5-rcis-(2RS)-2-~lE,3E)-(5S or 5R)-5-hydroxy-1,3-tridecadienyl-(lRS)-cycloheptyl]-pentanoic acid-1,5-lactone (diastereomer B, polar 5) in a more nonpolar fraction and 3.5 mg of (+/-)-(5S or 5R)-5-hydroxy-5-[cis-(2RS)-2-((lE,3E)-(5S or 5R)-5-hydroxy-1,3-triclecadienyl-(lRS)-cycloheptyl]-pentanoic acid (diastereomer B, polar 5) in a more polar fraction are obtained as colorless oil from 120 ~g of (+J-)-(5S or 5R)-5-acetoxy-5-[cis-(2RS)-2-((lE,3E)-(5S or 5R)-5-acetoxy-1,3-tridecadienyl-.

~ 72 ~ . `
(lRS)-cycloheptyl~-pentanoic acid (diastereomer B, polar ~) ~rom example 5).
IR (film; lactone): 3445 (broad), 3020, 2928, 2858, 1735, 1460, 1242, 990 cm~l.

IR (CHCl3); acid): 3450 (broad), 300~, 2930, 2860, 1730, -i~ 1462, 1375, ~250, g90 cm~1.

~ampl~ 28 (~ 5RS~-5-AcQtoxy-5-rtrans-(2RS~-2-((lE 3El-~5R or 552=
5 acetoxy-l 3-~ridacadienvl-(lRS~-cyclohept~ll pentan l-ol fdiastereomer A) A solution of 2.93 g of 4-chloro-1-(tertP-butyl-dimethylsilyloxy)-butane in 2.5 ml of tetrahydrofuran is instilled in 639 mg of magnesium at 24C under argon, a crystal of iodine is added, heated for 10 minutes to 70C, stirred for 30 minutes at 2~C and diluted with 8.2 ml of tetrahydrofuran.
The above-produced Grignard solution is instilled in a solution of 1.56 g of trans-(lRS)-l-formyl-(2RS)-2-[(lE,3E)-(5R
or ~S)-5-acetoxy-1,3-tridecadienyl-cycloheptane ~diastereomer A) from example 9a~ in 3 ml of tetrahydrofuran at -70C under argon and allowed to heat to -30C and stirred for 1 hour at this temperature. The reaction mixture is added to 100 ml of saturated aqueous ammoniumchloride solution and extracted three times with 100 ml of ethyl acetate each. The combined organic phases are washed once with semiconcentrated aqueous sodium `1 chloride solution, dried on anhydrous sodium sulfate and after ~iltration ooncentrated by evaporation in a vacuum. The thus i .~1 73 ~122~92 obtained residue is purified by multiple chromatography on silica gel. With hexane~ethyl ac~tate (85~15), 1.52 g of the alcohol is obtained as colorless oil.
IR ~CEICl3)~ 3610r 3460 ~broad), 3005, 2930, 2860, 1724 1467, 1378, 1255, 11~, 994, 8~0 c~

For acetylation 2.16 ml of acetic anhydride is added ko a ~olution of 1.51 g of the above-describad alcohol in 4~32 ml of pyridine and stirred for 18 hours at 0C. Then it i~ dilu~ed with 1 ml of water a~d concentrated by evaporation in a vacuum with addition of toluene. The thus obtained residue is purified by chromatography on silica gel. With hexane~O-10~ ethyl acetate, 1.23 g of the acetate is obtained as colorless oil.
IR(CHCl3): 3007, 2938, 2862, 1727, 1468, 1378, 1256, 1100, 993, ~42 cm~1.

For silylether cleavage 1.23 g of the above-produced acetate in 8.3 ml of tetrahydrofuran is stirred with 1.30 g of tetrabutylammonium fluoride trihydrate at 24C under argon for 3 hours~ Then it is diluted with 70 ml of diethyl ether, washed three times with 20 ml of water each, once with saturated aqueous sodium chloride solution, dried on anhydrous sodium sulfate and after filtration concentrated by evaporation in a vacuum. The thus obtained residue is purified by chromatography on silica gel. With hexane/O 30% ethyl ac~tate, 895 mg of the title compound is obtained as colorless oil.

7~ 2~22~92 . . .

~ IR (CHCl3): 3625, 3460 ~broad), 3005, 2930, 2860, 17~5, 1460, 1375, 1255, 992 cm~l.

The initial material ~or the a:bove title compound is produced as follows:

28a) trans-tlRS~ Formyl-(2R~S)-2 ~tlE.3E?-f5R or 5S3-5-aceto ~-l~3~tridecadienyl-cycloheptane~(dlastereomer A) Analogously to example 20e~ 1.56 g of the title compound is obtained ~rom 1.61 g of (5R or 5S)-5-acetoxy-1-[tranis-1-hydroxymethyl-cyclohept-2-yl]-(lE~3E)-trideca-l~3-diene ~diastereomer A, 1st fraction ~rom example ld)), that is used without further purification.
IR (CHCl3): 3020, 2928, 2858, 2720, 1722, 1460, 1373, 1247, 990 cm~l.

Example 29 (~/-L- (5RS)-5-Acetoxy-5-ttrans-(2RS)-2-((lE,3E)-(5S or 5R)-5-acetoxy-1,3-tridecadienyl~-tlRS!-cycloheptyll-pentan-1-ol fdiastereomer B
A solution o~ 2.48 g of 4-chloro-1-(tert.-butyl-dimethylsilyloxy)-butane in 2.~ ml of tetrahydrofuran is instilled in 541 mg of magnesium at 24C under argon, a crystal of iodine is added, heated for 10 minutes to 70C, stirred for 30 minutes at 24C and diluted with 7.0 ml of tetrahydrofuran.
The above-produced Grignard solution is instilled in a solution of 1.31 ~ of trans-(lRS)-l-formyl-(2RS)-2-[(lE,3E)-(5S

`1 ' . ~ ' ?A ~ "~ ? ?

~ 75 -' 2~22~32 or SR)-5-acetoxy-1,3-tridecadienyl-cycloheptane (diastereomer B) ~rom example lOa) in 2.5 ml of tetrahydrofuran at --70C under argon and allowed to heat to -30c and stirred for 1 hour at this temperature. The reaction mixture is added to 100 ml of saturated aqueous ammoniumchloride ~olution and extracted three times with 100 ml of ethyl acetate each. The combined organic phases are washed once with semiconcentrated aqueous sodi~m chloride solution, dried on anhydrous sodium sul~ate and after ~iltration concentrated by evaporation in a vacuum. The thus obtained rasidue is purified by multiple flash-chromatography on ~ilica gel. With hexane/methyl-tert.-butylether (g~8), 726 mg of the alcohol is obtained as colorless oil.
IR (CHCl3): 3610, 3450 (broad~, 3005, 2930, 2860, 1725, 1465, 1375, 1253, 1098, 992, 838 cm~1.

For acetylation l ml of acetic anhydride is added to a solution of 718 mg of the above-described alcohol in 2 ml of pyridine and stirred for 18 hours at 0C. Then it is diluted with 0.5 ml of water and concentrated by evaporation in a vacuum with addition of toluene. The thus obtained residue is purified by chromatography on silica gel. With hexane/0-10% ethyl acetate, 687 m~ of the acetate is obtained as colorless oil.
IR(CHCl3): 3005, 2930, 2860, 1726, 1466, 1374, 1253, 1098, 992, 838 cm~1.

For silylether cleavage 679 mg of the above-produced acetate in 4.6 ml of tetrahydrofuran is stirred with 723 mg of -I

; ~ ~ 76 21~

tetrabutylammonium ~luoride trihydrate at 24C under argon for 3 hours. Then it is diluted with 50 ml of diethyl ether, washed i.! three times with 10 ml of water each7 once with saturated aqueous ~, sodium chloride solution, dried on anhydrous sodium sul~ate and a~ter filtra$ion concentrated by evaporation in a vacuum. The thuis obtained residue is purified by chromatography on silica gel. With hexane/0-40% ethyl acetate, 552 mg of the title compound is obtained as colorless oil.
IR (CHCl3): 3620, 3460 (broad), 3005, 2930, 2860, 1723, 1~65, 1375, 1250, 992 cm~1.

The initial material for the above title compound is produced as follows:

29a) trans-(lRS?-1-Formyl-(2RS)-2-r(lE.3E2-~5S or 5R~-5-acetoxy~ 3.-tridecadienyl-cycloheptane ~diastereomer BL
Analogously to example 20e) 1.31 g of the title compound is obtained ~rom 1.36 g of (5S or 5R)-5-acetoxy-1-[trans-1-hydroxymethyl-cyclohept-2-yl]-(lE,3E)-trideca-1,3-diene (diastereomer B, 3rd fraction from example ld)), that is used without further purification.
IR (CHCl3): 3020, 2930, 2858, 2720, 1723, 1460, 137~, 1250, 9gO cm-1.

.,. ~ ~ ,. : , . . ' ~ 77 2:122~

E~ample 30 (~ (5RS~_5-Acetoxy-5-rtrans--(2RS)-2-~L E,3E2-15R or 5S)-5-acetoxy-1,3-tridecadienyl-(lRS~-cycloheptyl~-pentanoic acid fdiastereomer B) For oxidation 891 of the t:itle compound produced in example 28~ is dissolved in 45 ml vf dichloromethane, mixed with 7.51 g of Collins reagent at oC under argon and stirred for 1 hour at 0C. Then it is diluted with diethyl ether, mixed with Celite, filtered off on Celite and washed well with diéthyl ether. The l-aldehyde obtained after concentration by evaporation is immediately dissolved in 51 ml of acetone without further purification, mixed with 1.3 ml of Jones reagent (J.
Chem. Soc. 1953, 25S5) at 30C under argon and stirred for 20 minutes at this temperature. ~hen 0.5 ml of 2-propanol is added, stirred for 10 minutes, diluted with 100 ml of ethyl acetate, shaken four times with 30 ml of saturated aqueous sodium chloride solution each, dried on anhydrous sodium sulfate and aftex filtration concentrated by evaporation in a vacuum. The thus obtained residue is purified by chromatography on silica gel.
With hexane/0-50% ethyl acetate, 483 mg of the title compound is obtained as colorless oil.
IR ~film): 3450, 3200 (broad), 3020, 2930, 2858, 1738, 1710, 1458, 1372, 1242, 990 cm~1.

. 78 2~.2~92 ~' ~! E~ampl~ 31 cetoxy-5-rtrans-(2RS)-2-((lEL3E) (5S or 5R)--acetoxY-1~,3-tridecadienvl~-(lRS)-cvcloheptYll-~entanoic acid (diastereom~r B) For oxidation 541 mg of the title compound produced in example 29) is dissolved in 27 ml of dichloromethane, mixed with 4.57 g o~ Collins reagent at 0C under argon and stirred for 1 hour at 0C. Then it is diluted with diethyl ether, mixed with Celite~ filtered off on Celite and washed well with diethyl ether. The l-aldehyde obtained after concentration by evaporation is immediately dissolved in 30 ml of acetone without further purification, mixed with 0.75 ml of Jones reagent at 30C
under argon and stirred for 20 minutes at this temperature. Then 0.3 ml of 2-propanol is added, stirred for 10 minutes, diluted with 100 ml of ethyl acetate, shaken ~our times with 30 ml of semiconcentrated agueous sodium chloride solution each t dried on anhydrous sodium sulfate and after filtration concentrated by evaporation in a vacuum. The thus obtained residue is purified by chromatography on silica gel. With hexane/0-40% ethyl acetate, 326 mg of the title compound is obtained as colorless oil.
IR (CHCl3): 3450, 3200 (broad), 3020, 2928, 2858, 1738, 1710, 1460, 1372, 1240, 992 cm~l.

, I .

2122~92 3 E~ample 32 (+/-~-(5RS~-5 AcetoxY-5- r trans~ RS)-2-((lE.3E~-(5R or 5Sl-5-hydroxy-1,3-tridecadienyl ! (lRS~ YclohePtYlL~pentanoic acid ,~, rdiastereomer AL
Analogously to example 21), 121 mg of the title compound is obtained as colorless oil from 150 mg of (+/-)-(5RS)-5-acetoxy-5-~ rtrans-(2~S)-2-((lE,3E)-~5R or 5S)-5-acetoxy-~,3-tridecadienyl~
3 (lRS)-cycloheptyl~-pentanoic acid (diastereomer A~ from example 11) .
IR ~fil~): 3440, 3200 (broad), 3020, 2928, 2857, 1737, 1712, 1458, 1375, 1242, 990 cm~1.

Example 33 (+/-)-f5RS~-5-AcetoxY-5- r trans-(2RS)-2-((lE,3E2-(5S or 5R)-5-hYdroxy-1,3-tridecadienyl)-(lRS)-cyclohePtYll-pentanoic acid (diastereomer B) Analogously to example 21), 89.8 mg of the title compound is obtained as colorless oil from 125 mg of (+/-)-(5RS)-5-acetoxy-5-[tran~-(2RS)-2-((lE,3E)-(5S or 5R)-5-acetoxy-1,3-tridecadienyl-(lRS)-cycloheptyl]-pentanoic acid (diastereomer B) from example 12).
IR (film): 3440, 3100 (broad), 3020, 2925, 2860, 1730, 1705, 1467, 1375, 1260, 988 cm~1.

, , ~I .

~ q~srt~

~ 212~992 B~ample ~4 (+/-1-(5~S)-5-Hydroxy-5-rtrans--(2RS)-2-(~lE.3E)-(5R or 5S
5-hYdroxy-1 3-tridecadienyl)-(lRS?-c~cloheptyl~-~entanoic acid (diastereomer A2 and (+~ 5RS)-5-hYdroxy-5-rtrans-(2RS)-2-(~lE~3E!-(5R or 5S~-S-hydroxy-1,3-tlidecadienyl~-tlRS)-cycloheptyll-pentanoic acid 1 5-lacto~e ~diastereomer A) Analogously to example 2~, 40.1 mg of (+/-)-(5RS)-5-hydroxy-5-[trans-(2RS) 2-~(lE,3E)-(5R or 5S)-5-hydroxy-1,3-tridecadienyl-~lRS)-cycloheptyl]-pentanoic acid-1,5-lactone (diastereomer A) in a more nonpolar ~raction and 8.8 mg of t+/-)-(5RS)-5-hydroxy-5-[trans-(2RS)-2-((lE,3E)-(5R or 5S)-5-hydroxy-1,3-tridecadienyl-(lRS)-cycloheptyl]-pentanoic acid ~diastereomer A) in a more polar fraction are obtained as colorless oils from 170 mg of (+/~)-(5RS)-5-acetoxy-5-[trans-(2RS)-2-((lE,3E)-(5R or 5S)-5-acetoxy-1,3-tridecadienyl-(lRS)-cycloheptyl~-pentanoic acid (diastereomer A) from example 11).
IR (film; lactone): 3440 (broad), 3018, 2930, 2855, 1733, 1465, 1245, 900 cm1.
IR (film; acid): 3435 (broad), 3200 (broad), 3020, 2925, 2855, 1725, 1463, 1380, 1255, 992 cm~l.

:' . I

"

, .

81 2 1 2 ~ ~ :3 2 .. .
E2~mple 35 (+/~ (5RS)-5-Hydroxy~5-[trans--~2RS)~2-((lE~3E~(5S or 5R)-5-hydr~o~y-1 3-tridecadienyl)-~lRS~-cycloheptyl]-pentanoic acid (diastereomer_B~_and~(+~-)-(5RS)-5-hydroxy-5-rtrans-12RS~-2-((lE,3E)-(5S or 5R)-5-hydroxy-1 3-tridecadien~l)-(lRS)-cvcloheptyll-pentanoiq acid-1,5-lactone (diastereomer B) Analogously to example 22, 29 mg of (+/-)-(5RS)-5-hydroxy-5-[trans-(2RS)-2-((lE,3E)-(5S or SR)-5-hydroxy-1,3-tridecadienyl-(lRS~-cyclohaptyl3-pentanoic acid~l,5-lactone (diastereomer B) in a more nonpolar fraction and 17.9 mg of (+/-)-(5RS)-5-hydroxy-5-[trans-(2RS)-2-((lE,3E)-(5S or 5R~-5-hydroxy-1,3-txidecadienyl-(lRS)-cycloheptyl~pentanoic acid (diastereomer B) in a more polar fraction are obtained as colorless oils from 125 mg of (+/-)-(5RS~-5-acetoxy-5-[trans-(2RS)-2~~(lE,3E)-(5S or 5R)-5-acetoxy-1,3-tridecadienyl)-(lRS)-cycloheptyl]-pentanoic acid (diastereomer B) from example 12).
IR (film; lactone): 3440 ~broad), 3020, 2925, 2858, 1732, 1464, 1245, 990 cm~l.
IR (film; acid) 3415 (broad), 3015, 2924, 2857, 1713, 1462, 1378, 1250, 990 cm~1.

~xample 36 (+/-)-f5RS~-5-Acetoxy-5-[trans-(2RSl-2-((lE,3E)-(5R or 5S)-5-acetoxy-1,3-triclecadienvl)-( lRS )-cycloheptyl~-pentanoic acid methyl ester (diastereomer A) An ethereal cliazomethane solution is instilled until permanent yellow coloring in a solution of 43 mg (~/~ 5RS)-5--.

. . 82 ~1229~2 ,~

acetoxy-5-[trans (2RS)-2-((lE,3E)-(5R or 5S)-5-acetoxy-1,3-tridecadianyl-(lRS)-cycloheptyl]-pentanoic acid (diastereomer A) from example 30 in ~ ml of dichloromsthane at 0C undsr argon, stirred for 15 minutes at 0C and th~en concentrated by evaporation in a vacuum. The thus obtained rPsidue is purified by chromatography on silica gel. Wi.th hexane/0-10% ethyl acetate, 36 mg o~ th~ title compound is obtained as colorless oil.
IR (CHCl3). 3005, 2935, 2860, 1730, 1460, 1376, 1255, 990 cm-1.

Examplo 37 (+/~ 5RS)-5-Acetoxv-5-rtrans-(2RS2-~-~(lEr3E)-(5S or 5R)-5-hydroxy-1,3-tridecadienyl~-(lRS)--cycloheptyl~-pentanoic acid-tris-(hydroxymethyl)-amino methane salt (diastereomer B) A solution of 4 mg of tris-(hydroxymethyl~-aminomethane in 0~02 ml of water is added at 70C to a solution of 10 mg of (+~-) (5RS)-5-hydroxy-5-[trans-(2RS)-2-((lE,3E)-(5S or 5R)-5-hydroxy-1,3-tridecadienyl-(lRS)-cycloheptyl]-pentanoic acid (diastereomer B) from example 16) in 1.5 ml of acetonitrile. It is allowed to cool with stirring, decanted after 16 hours from the solvent and the residue is dried in a vacuum. 3.3 mg of the title compound is isolated as waxy material.

Claims

1. Leukotriene-B4 derivatives of formula I

(I), in which R1 means CH2OH, CH3, CF3, COOR5, CONR6R7, or R1 together with R2 means a carbonyl group, R2 and R3 are the same or different and represent H or an organic acid radical with 1-15 C atoms, R4 symbolizes H, (C1-C10) alkyl optionally substituted once or several times by chlorine or bromine, C3-C10 cycloalkyl, C6-C10 aryl radical optionally substituted, independent from one another, once or several times by chlorine, bromine, phenyl, C1-C4 alkyl, C1-C4 alkoxy, fluoromethyl, chloromethyl, trifluoromethyl, carboxy or hydroxy, or a 5-6-membered aromatic heterocyclic ring with at least 1 heteroatom, R5 means hydrogen, C1-C10 alkyl, C3-C10 cycloalkyl, C6-C10 aryl radical optionally substituted by 1-3 chlorine, bromine, phenyl, C1-C4 alkyl, C1-C4 alkoxy, fluoromethyl, chloromethyl, trifluoromethyl, carboxy or hydroxy, CH2-CO-(C6-C10) aryl or a 5-6-membered ring with at least 1 heteroatom, A symbolizes a trans, trans-CH=CH-CH=CH, a -CH2CH2-CH=CH- or a tetramethylene group, B symbolizes a C1-C10 straight-chain or branched-chain alkylene group, which optionally can be substituted by fluorine or the group .

D can mean a direct bond, oxygen, sulfur, -C?C-, -CH=CR8 or together with B can also mean a direct bond, R6 and R7 are the same or different and represent H or C1-C4 alkyl or R7 represents H and R6 represents C1-C10 alkanoyl or C1-C10 alkanesulfonyl, R8 means H, C1-C5 alkyl, chlorine, bromine, m symbolizes the numbers 1 or 4 and n is 3-5 as well as, if R5 means hydrogen, their salts with physiologically compatible bases and their cyclodextrin clathrates.

2. (+/-)-(5RS)-5-Acetoxy-5-[cis-(2RS)-2-((1E,3E)-(5RS)-5-acetoxy-1,3-tridecadienyl)-(1RS)-cyclobutyl]-pentan-1-ol.

3. (+/-)-(5RS)-5-Acetoxy-5-[cis-(2RS)-2-((1E,3E)-(5RS)-5-acetoxy-1,3-tridecadienyl)-(1RS) cyclobutyl]-pentanoic acid.

4. (+/-)-(5RS)-5-Hydroxy-5-[cis-(2RS)-2-((1E,3E)-(5RS)-5-hydroxy-1,3-tridecadienyl)-(1RS)-cycloheptyl]-pentanoic acid.

5. (+/-)-(5RS)-5-Acetoxy-5-[cis-(2RS)-2-((1E,3E)-(5RS)-5-hydroxy-1,3-tridecadienyl)-(1RS)-cyclobutyl]-pentanoic acid.

6. (+/-)-(5RS)-5-Hydroxy-5-[cis-(2RS)-2-((1E,3E)-(5RS)-5-hydroxy-1,3-tridecadienyl)-(1RS)-cyclobutyl]-pentan-1-ol.

7. (+/-)-(5RS)-5-Acetoxy-5-[trans-(2RS)-2-((1E,3E)-(5RS)-5-acetoxy-1,3-tridecadienyl)-(1RS)-cyclobutyl]-pentanoic acid.

8. (+/-)-(5RS)-5-Acetoxy-5-[trans-(2RS)-2-((1E,3E)-(5RS)-5-acetoxy-1,3-tridecadienyl)-(1RS)-cyclobutyl]-pentan-1-ol.

9. (+/-)-(5RS)-5-Hydroxy-5-[trans-(2RS)-2-((1E,3E)-(5RS)-5-hydroxy-1,3-tridecadienyl)-(1RS)-cyclobutyl]-pentanoic acid.

10. (+/-)-(5RS)-5-Acetoxy-5-[trans-(2RS)-2-((1E,3E)-(5RS)-5-hydroxy-1/3-tridecadienyl)-(1RS)-cyclobutyl]-pentanoic acid.

11. (+/-)-(5RS)--5-Hydroxy-5-[cis-(2RS)-2-((1E,3E)-(5RS)-5-hydroxy-1,3-tridecadienyl)-(1RS)-cyclobutyl]-pentanoic acid methyl ester.

12. (+/-)-(5RS)-5-Acetoxy-5-[cis-(2RS)-2-((1E,3E)-(5RS)-5-hydroxy-1,3-tridecadienyl)-(1RS)-cyclobutyl]-pentanoic acid methyl ester.

13. (+/-)-(5RS)-5-Hydroxy-5-[cis-(2RS)-2-((1E,3E)-(5RS)-5-hydroxy-1,3-tridecadienyl)-(1RS)-cyclobutyl]-pentanoic acid-tris-(hydroxymethyl)-aminomethane salt.

14. (+/-)-(5RS)-5-Hydroxy-5-[cis-(2RS)-2-((1E,3E)-(5RS)-5-hydroxy-1,3-tridecadienyl)-(1RS)-cyclobutyl]-pentanoic acid-1,5-lactone.

15. Pharmaceutical preparations characterized by a content of one or two leukotriene-B4 derivatives according to claims 1 to 14.

16. (+/-)-(5RS)-5-Acetoxy-5-[cis-(2RS)-2-((1E,3E)-(5RS)-5-acetoxy-1,3-tridecadienyl)-(1RS)-cyclobutyl]-pentan-1-ol.

17. (+/-)-(5RS)-5-Acetoxy-5-[cis-(2RS)-2-((1E,3E)-(5RS)-5-acetoxy-1,3-tridecadienyl)-(1RS)-cyclobutyl]-pentanoic acid.

18. (+/-)-(5RS)-5-Hydroxy-5-[cis-(2RS)-2-((1E,3E)-(5RS)-5-hydroxy-1,3-tridecadienyl)-(1RS)-cycloheptyl]-pentanoic acid.

19. (+/-)-(5RS)-5-Acetoxy-5-[cis-(2RS)-2-((1E,3E)-(5RS)-5-hydroxy-1,3-tridecadienyl)-(1RS)-cyclobutyl]-pentanoic acid.

20. (+/-)-(5RS)-5-Hydroxy-5-[cis-(2RS)-2-((1E,3E)-(5RS)-5-hydroxy-1,3-tridecadienyl)-(1RS)-cyclobutyl]-pentan-1-ol.

21. (+/-)-(5RS)-5-Acetoxy-5-[trans-(2RS)-2-((1E,3E)-(5RS)-5-acetoxy-1,3-tridecadienyl)-(1RS)-cycloheptyl]-pentan-1-ol.

22. (+/-)-(5RS)-5-Acetoxy-5-[trans-(2RS)-2-((1E,3E)-(5RS)-5-acetoxy-1,3-tridecadienyl)-(1RS)-cycloheptyl]-pentanoic acid.

23. (+/-)-(5RS)-5-Acetoxy-5-[trans-(2RS)-2-((1E,3E)-(5RS)-5-hydroxy-1,3-tridecadienyl)-(1RS)-cycloheptyl]-pentanoic acid.

24. (+/-)-(5RS)-5-Hydroxy-5-[trans-(2RS)-2-((1E,3E)-(5RS)-5-hydroxy-1,3-tridecadienyl)-(1RS)-cycloheptyl]-pentanoic acid.

25. (+/-)-(5RS)-5-Hydroxy-5-[trans-(2RS)-2-((1E,3E)-(5RS)-5-hydroxy-1,3-tridecadienyl)-(1RS)-cycloheptyl]-pentanoic acid-1,5-lactone.

26. (+/-)-(5RS)-5-Acetoxy-5-[trans-(2RS)-2-((1E,3E)-(5RS)-5-acetoxy-1,3-tridecadienyl)-(1RS)-cycloheptyl]-pentanoic acid-methyl ester.

27. (+/-)-(5RS)-5-Hydroxy-5-[trans-(2RS)-2-((1E,3E)-(5RS)-5-hydroxy-1,3-tridecadienyl)-(1RS)-cycloheptyl]-pentanoic acid-tris-(hydroxymethyl)-aminomethane salt.

28. Pharmaceutical preparations characterized by one or two leukotriene-B4 derivatives according to claims 1 to 28.

29. Process for the production of leukotriene-B4 derivatives of formula I according to claim 1, wherein an aldehyde of formula II

(II), in which m, A, B, D, R3 and R4 have the above-indicated meanings, optionally after protection of free hydroxy groups with a magnesium-organic compound of formula III, X-Mg-CH2-CH2-CH2-CH2-R9 (III), in which X represents chlorine, bromine or iodine and R9 represents -CH3, CF3 or OR10, in which R10 means an easily cleavable ether radical, is reacted and optionally then isomers are separated in any sequence, protected hydroxy groups are released and/or a free hydroxy group is esterified and/or the 1-hydroxy group is oxidized to carboxylic acid and/or double bonds are hydrogenated and/or an esterified carboxyl group (R1 = COOR5) is saponified and/or reduced and/or a carboxyl group (R5 = H) is esterified and/or a free carboxy group (R5 = H) is converted to an amide (R1 = CONHR7) or a carboxyl group with a physiologically compatible base is converted to a salt.